Phenylpiperidines and phenylpyrrolidines

ABSTRACT

Substituted phenylpiperidines and phenylpyrrolidines of formula (I), compositions containing them, and methods of making and using them to treat histamine-mediated conditions.

CROSS-REFERENCE TO RELATED APPLICATIONS

[0001] Provisional Application No. 60/420,494, filed Oct. 23, 1902,hereby incorporated by reference.

STATEMENT REGARDING FEDERALLY SPONSORED RESEARCH OR DEVELOPMENT

[0002] The research and development of the invention described below wasnot federally sponsored.

FIELD OF THE INVENTION

[0003] The present invention relates to phenylpiperidines andphenylpyrrolidines, their synthesis and their use, for example, for thetreatment of disorders and conditions mediated by the histaminereceptor.

BACKGROUND OF THE INVENTION

[0004] Histamine {2-(imidazol-4-yl)ethylamine} is a transmittersubstance. Histamine exerts a physiological effect via multiple distinctG-protein coupled receptors. It plays a role in immediatehypersensitivity reactions and is released from mast cells followingantigen IgE antibody interaction. The actions of released histamine onthe vasculature and smooth muscle system account for the symptoms of theallergic response. These actions occur at the H₁ receptor (Ash, A. S. F.and Schild, H. O., Br. J. Pharmac. Chemother. 1966, 27:427-439) and areblocked by the classical antihistamines (e.g. diphenhydramine).Histamine is also an important regulator of gastric acid secretionthrough its action on parietal cells. These effects of histamine aremediated via the H₂ receptor (Black, J. W. et al., Nature 1972,236:385-390) and are blocked by H₂ receptor antagonists (e.g.cimetidine). The third histamine receptor —H₃— was first described as apresynaptic autoreceptor in the central nervous system (CNS) (Arrang,J.-M. et al., Nature 1983, 302:832-837) controlling the synthesis andrelease of histamine. Recent evidence has emerged showing that the H₃receptors are also located presynaptically as heteroreceptors onserotonergic, noradrenergic, dopaminergic, cholinergic, and GABAergic(gamma-aminobutyric acid containing) neurons. These H₃ receptors havealso recently been identified in peripheral tissues such as vascularsmooth muscle. Consequently there are many potential therapeuticapplications for histamine H₃ agonists, antagonists, and inverseagonists. (See: “The Histamine H ₃ Receptor—A Target for New Drugs”,Leurs, R., and Timmerman, H., (Eds.), Elsevier, 1998; Morisset, S. etal., Nature 2000, 408:860-864.) A fourth histamine receptor —H₄— wasrecently described by Oda, T. et al. (J. Biol. Chem. 2000,275(47):36781-36786).

[0005] The potential use of histamine H₃ agonists in sleep/wake andarousal/vigilance disorders is suggested based on animal studies (Lin,J.-S. et al., Brain Res. 1990, 523:325-330; Monti, J. M. et al., Eur. J.Pharmacol. 1991, 205:283-287). Their use in the treatment of migrainehas also been suggested (McLeod, R. L. et al., Soc. Neurosci. Abstr.1996, 22:2010) based on their ability to inhibit neurogenicinflammation. Other applications could be a protective role inmyocardial ischemia and hypertension where blockade of norepinephrinerelease is beneficial (Imamura, M. et al., J. Pharmacol. Exp. Ther.1994, 271(3):1259-1266). It has been suggested that histamine H₃agonists may be beneficial in asthma due to their ability to reducenon-adrenergic non-cholinergic (NANC) neurotransmission in airways andto reduce microvascular leakage (Ichinose, M. and Barnes, P. J., Eur. J.Pharmacol. 1989, 174:49-55).

[0006] Several indications for histamine H₃ antagonists and inverseagonists have similarly been proposed based on animal pharmacologyexperiments with known histamine H₃ antagonists (e.g. thioperamide).These include dementia, Alzheimer's disease (Panula, P. et al., Soc.Neurosci. Abstr. 1995, 21:1977), epilepsy (Yokoyama, H. et al., Eur. J.Pharmacol. 1993, 234:129-133) narcolepsy, eating disorders (Machidori,H. et al., Brain Res. 1992, 590:180-186), motion sickness, vertigo,attention deficit hyperactivity disorders (ADHD), learning and memory(Barnes, J. C. et al., Soc. Neurosci. Abstr. 1993, 19:1813), andschizophrenia (Schlicker, E. and Marr, I., Naunyn-Schmiedeberg's Arch.Pharmacol. 1996, 353:290-294). (Also see: Stark, H. et al., Drugs Future1996, 21(5):507-520; and Leurs, R. et al., Prog. Drug Res. 1995,45:107-165 and references cited therein.) Histamine H₃ antagonists,alone or in combination with a histamine H₁ antagonist, are reported tobe useful for the treatment of upper airway allergic response (U.S. Pat.Nos. 5,217,986; 5,352,707 and 5,869,479). Recently, a histamine H₃antagonist (GT-2331) was identified and is being developed by GliatechInc. (Gliatech Inc. Press Release Nov. 5, 1998; Bioworld Today, Mar. 2,1999) for the treatment of CNS disorders.

[0007] As noted, the literature related to histamine H₃ ligands has beencomprehensively reviewed (“The Histamine H ₃ Receptor—A Target for NewDrugs”, Leurs, R. and Timmerman, H., (Eds.), Elsevier, 1998). Withinthis reference the medicinal chemistry of histamine H₃ agonists andantagonists was reviewed (see Krause, M. et al., and Phillips, J. G. andAli, S. M., respectively). The importance of an imidazole moietycontaining only a single substitution in the 4-position was notedtogether with the deleterious effects of additional substitution onactivity. Particularly, methylation of the imidazole ring at any of theremaining unsubstituted positions was reported to strongly decreaseactivity. Additional publications support the hypothesis that animidazole function is essential for high affinity histamine H₃ receptorligands (see Ali, S. M. et al., J. Med. Chem. 1999, 42:903-909, andStark, H. et al., and references cited therein). However manyimidazole-containing compounds are substrates for histamine methyltransferase, the major histamine metabolizing enzyme in humans, whichleads to shortened half-lives and lower bioavailability (see Rouleau, A.et al., J. Pharmacol. Exp. Ther. 1997, 281(3):1085-1094). In addition,imidazole-containing drugs, via their interaction with the cytochromeP450 monooxygenase system, can be targets of unfavorablebiotransformations due to enzyme induction or enzyme inhibition (see:Kapetanovic, I. M. and Kupferberg, H. J., Drug Metab. Dispos. 1984,12(5):560-564; Sheets, J. J. and Mason, J. I., Drug Metab. Dispos. 1984,12(5):603-606; Back, D. J. and Tjia, J. F., Br. J. Pharmacol. 1985,85:121-126; Lavrijsen, K. et al., Biochem. Pharmacol. 1986,35(11):1867-1878; Albengres, E. et al., Drug Safety 1998,18(2):83-97).The poor blood brain barrier penetration of earlier histamine H₃receptor ligands may also be associated with the imidazole fragment(Ganellin, C. R. et al., Arch. Pharm. Pharm. Med. Chem. (Weinheim, Ger.)1998, 331:395-404).

[0008] More recently, several publications have described histamine H₃ligands that do not contain an imidazole moiety, for example: Ganellin,C. R. et al.; Walczynski, K. et al., Arch. Pharm. Pharm. Med. Chem.(Weinheim, Ger.) 1999, 332:389-398; Walczynski, K. et al., Farmaco 1999,54:684-694; Linney, I. D. et al., J. Med. Chem. 2000, 43:2362-2370;Tozer, M. J. and Kalindjian, S. B., Exp. Opin. Ther. Patents2000,10:1045-1055; U.S. Pat. No. 5,352,707; PCT Application WO 99/42458,Aug. 26, 1999; PCT Application WO 02/076925; and European PatentApplication 0978512, Feb. 9, 2000.

[0009] The compounds of the present invention do not contain theimidazole moiety, and its inherent liabilities, and yet maintain potencyat the human H₃ receptor as determined by receptor binding to the humanhistamine H₃ receptor (see Lovenberg, T. W. et al., Mol. Pharmacol.1999, 55:1101-1107). Screening using the human receptor is particularlyimportant for the identification of new therapies for the treatment ofhuman disease. Conventional binding assays are determined using ratsynaptosomes (Garbarg, M. et al., J. Pharmacol. Exp. Ther. 1992,263(1):304-310), rat cortical membranes (West, R. E. et al., Mol.Pharmacol. 1990, 38:610-613), and guinea pig brain (Korte, A. et al.,Biochem. Biophys. Res. Commun. 1990, 168(3):979-986). Only limitedstudies have been performed previously using human tissue but theseallude to significant differences in the pharmacology of rodent andprimate receptors (West, R. E. et al., Eur. J. Pharmacol. 1999,377:233-239).

[0010] We now describe a series of phenylpiperidines andphenylpyrrolidines with the ability to modulate the activity of thehistamine receptor, specifically the H₃ receptor, without the inherentproblems associated with the presence of an imidazolyl moiety.

SUMMARY OF THE INVENTION

[0011] The present invention is directed to pharmaceutically activephenylpiperidines and phenylpyrrolidines, methods of making them, andmethods of using them. The invention features a compound of formula (I):

[0012] wherein

[0013] L is a direct bond, or an optionally C₁₋₄alkyl substitutedradical selected from the group consisting of C₁₋₄alkylene orC₃₋₄alkenylene wherein NR¹R² is attached to an sp³ hybridized carbon,C₃₋₄alkynylene wherein NR¹R² is attached to an sp³ hybridized carbon,C₂₋₄alkylidene wherein NR¹R² is attached to an sp³ hybridized carbon,aryloxy wherein NR¹R² is not attached to the oxygen, arylthio whereinNR¹R² is not attached to the sulfur, C₂₋₄alkoxy wherein NR¹R² is notattached to the oxygen or a carbon attached to the oxygen, C₂₋₄alkylthiowherein NR¹R² is not attached to the sulfur or a carbon attached to thesulfur, and —C₂₋₃alkyl-X—C₁₋₂alkyl- wherein X is O, S or NH and whereinNR¹R² is not attached to a carbon attached to X;

[0014] p is 0, 1 or 2;

[0015] q is 1 or 2; provided that 2≦p+q≦4;

[0016] R¹ is a substituent independently selected from the groupconsisting of hydrogen, C₁₋₆ alkyl, C₃₋₆ alkenyl, C₃₋₉ carbocyclyl, 3-12membered heterocyclyl (preferably 5-9 or 5-8-membered heterocyclyl),phenyl, (5-9-membered heterocyclyl)C₁₋₆ alkylene, and (phenyl)C₁₋₆alkylene;

[0017] R² is a substituent independently selected from the groupconsisting of C₁₋₆ alkyl, C₃₋₆ alkenyl, C₃₋₉ membered carbocyclyl, 3-12membered heterocyclyl (preferably 5-9 or 5-8-membered heterocyclyl),phenyl, (5-9-membered heterocyclyl)C₁₋₆ alkylene, and (phenyl)C₁₋₆alkylene;

[0018] or R¹ and R² taken together with the nitrogen to which they areattached form a saturated 3-13 membered N-linked heterocyclyl, wherein,in addition to the N-linking nitrogen, the 3-13 membered heterocyclylmay optionally contain between 1 and 3 additional heteroatomsindependently selected from O, S, and NH;

[0019] wherein R¹ and R² are optionally and independently substitutedwith 1-3 substituents selected from the group consisting oftert-butyloxycarbonyl, hydroxy, halo, nitro, amino, cyano, carboxamide,C₁₋₆ alkyl, C₁₋₆ acyl, 5-9-membered heterocyclyl, —N(C₁₋₆ alkyl)(5-9membered heterocyclyl), —NH(5-9 membered heterocyclyl), —O(5-9 memberedheterocyclyl), (5-9 membered heterocyclyl)C₁₋₃ alkylene,C₁₋₂-hydroxyalkylene, C₁₋₆ alkoxy, (C₃₋₆ cycloalkyl)-O—, phenyl,(phenyl)C₁₋₃ alkylene, and (phenyl)C₁₋₃ alkylene-O—; and wherein each ofthe preceding substituents of R¹ and R² may optionally have between 1and 3 substituents independently selected from the group consisting oftrifluoromethyl, halo, nitro, cyano, hydroxy, and C₁₋₃ alkyl;

[0020] one of R³, R⁴ and R⁵ is G and the other two independently arehydrogen, fluoro, chloro, bromo, nitro, trifluoromethyl, methyl, or C₁₋₃alkoxy;

[0021] G is L²Q;

[0022] L² is unbranched —(CH₂)_(n)— wherein n is an integer from 1 to 7(preferably n is 1 to 4, more preferably n is 1);

[0023] Q is NR⁸R⁹ wherein R is independently selected from hydrogen,C₁₋₆ alkyl, C₃₋₆ alkenyl, C₃₋₉ carbocyclyl, 3-12 membered heterocyclyl(preferably 5-9 or 5-8-membered heterocyclyl), phenyl, (5-9-memberedheterocyclyl)C₁₋₆ alkylene, and (phenyl)C₁₋₆ alkylene; and R⁹ isindependently selected from C₁₋₆ alkyl, C₃₋₆ alkenyl, 3-9 memberedcarbocyclyl, 3-13 membered heterocyclyl (preferably 5-9 or 5-8-memberedheterocyclyl), phenyl, (5-9-membered heterocyclyl)C₁₋₆ alkylene, and(phenyl)C₁₋₆ alkylene; or Q is a saturated 3-15 membered N-linkedheterocyclyl, wherein, in addition to the N-linking nitrogen, the 3-15membered heterocyclyl may optionally contain between 1 and 4 additionalheteroatoms independently selected from O, S, and NH;

[0024] wherein Q is optionally substituted with 1-3 substituentsselected (in addition to the preceding paragraph) from the groupconsisting of tert-butyloxycarbonyl, hydroxy, halo, nitro, amino, cyano,carboxamide, C₁₋₆ alkyl, C₁₋₆ acyl, 5-9-membered heterocyclyl, —N(C₁₋₆alkyl)(5-9 membered heterocyclyl), —NH(5-9 membered heterocyclyl),—O(5-9 membered heterocyclyl), (5-9 membered heterocyclyl)C₁₋₃ alkylene,C₁₋₂-hydroxyalkylene, C₁₋₆ alkoxy, (C₃₋₆ cycloalkyl)-O—, phenyl,(phenyl)C₁₋₃ alkylene, and (phenyl)C₁₋₃ alkylene-O—; and where saidsubstituent groups of Q may optionally have between 1 and 3 substituentsindependently selected from trifluoromethyl, halo, nitro, cyano,hydroxy, and C₁₋₃ alkyl;

[0025] R^(a) are independently C₁₋₃ alkyl, triflouromethyl;

[0026] m is 0, 1, 2 or 3; and

[0027] wherein each of the above alkyl, alkylene, alkenyl, heterocyclyl,cycloalkyl, carbocyclyl, and aryl groups may each be independently andoptionally substituted with between 1 and 3 substituents independentlyselected from methoxy, halo, amino, nitro, hydroxy, and C₁₋₃ alkyl;

[0028] or a pharmaceutically acceptable salt, ester, tautomer, solvateor amide thereof.

[0029] The invention also features a pharmaceutical compositioncomprising a compound of the invention and a pharmaceutically acceptablecarrier; and methods of preparing or formulating such compositions. Acomposition of the invention may further include more than one compoundof the invention, or a combination therapy (combination formulation orcombination of differently formulated active agents).

[0030] The invention also provides methods of treating certainconditions and diseases, each of which methods includes administering atherapeutically effective (or jointly effective) amount of a compound orcomposition of the invention to a subject in need of such treatment. Thedisclosed compounds are useful in methods for treating or preventingneurologic disorders including sleep/wake and arousal/vigilancedisorders (e.g. insomnia and jet lag), attention deficit hyperactivitydisorders (ADHD), learning and memory disorders, cognitive dysfunction,migraine, neurogenic inflammation, dementia, mild cognitive impairment(pre-dementia), Alzheimer's disease, epilepsy, narcolepsy, eatingdisorders, obesity, motion sickness, vertigo, schizophrenia, substanceabuse, bipolar disorders, manic disorders and depression, as well asother histamine H₃ receptor mediated disorders such as upper airwayallergic response, asthma, itch, nasal congestion and allergic rhinitisin a subject in need thereof. For example, the invention featuresmethods for preventing, inhibiting the progression of, or treating upperairway allergic response, asthma, itch, nasal congestion and allergicrhinitis.

[0031] In yet another embodiment, the disclosed compounds may be used ina combination therapy method including administering a jointly effectivedose of an H₃ antagonist and administering a jointly effective dose of ahistamine H₁ antagonist, such as loratidine (CLARITIN™), desloratidine(CLARINEX™), fexofenadine (ALLEGRA™) and cetirizine (ZYRTEC™), for thetreatment of allergic rhinitis, nasal congestion, and allergiccongestion.

[0032] In yet another embodiment, the disclosed compounds may be used ina combination therapy method, including administering a jointlyeffective dose of an H₃ antagonist and administering a jointly effectivedose of a neurotransmitter re-uptake blocker, such as a selectiveserotonin re-uptake inhibitor (SSRI) or a non-selective serotonin,dopamine or norepinephrine re-uptake inhibitor, including fluoxetine(PROZAC™), sertraline (ZOLOFT™), paroxetine (PAXIL™) and amitryptyline,for the treatment of depression, mood disorders or schizophrenia.

[0033] Additional features and advantages of the invention will becomeapparent from the detailed description and examples below, and theappended claims.

DETAILED DESCRIPTION OF THE INVENTION

[0034] The present invention provides phenylpiperidine andphenylpyrrolidine compounds useful for the treatment of disorders andconditions modulated by a histamine receptor.

[0035] A. Terms Certain terms are defined below and by their usagethroughout this disclosure.

[0036] As used herein, “C_(a-b)” (where a and b are integers) refers toa radical containing from a to b carbon atoms inclusive. For example,C₁₋₃ denotes a radical containing 1, 2 or 3 carbon atoms.

[0037] As used herein, “halo” or “halogen” shall mean monovalentradicals of chlorine, bromine, fluorine and iodine.

[0038] As used herein, the term “alkyl”, whether used alone or as partof a substituent group, shall include straight and branched saturatedcarbon chains. For example, alkyl radicals include methyl, ethyl,propyl, isopropyl, butyl, isobutyl, sec-butyl, t-butyl, pentyl and thelike. Unless otherwise noted, “lower” when used with alkyl means acarbon chain composition of 1-4 carbon atoms. “Alkylene” refers to adivalent hydrocarbyl group, such as methylene (—CH₂—), ethylene(—CH₂—CH₂—) or propylene (—CH₂CH₂CH₂—), and so on.

[0039] As used herein, unless otherwise noted, “alkenyl” shall mean analkylene group with at least two hydrogen atoms replaced with a pi bondto form a carbon-carbon double bond, such as propenyl, butenyl,pentenyl, and so on. Where the alkenyl group is R⁸ or R⁹, the openradical (point of attachment to the rest of the molecule) is on an sp³carbon, as illustrated by allyl, and the double bond or bonds istherefore at least alpha (if not beta, gamma, etc.) to the open radical.

[0040] As used herein, “alkylidene” refers to a saturated orunsaturated, branched, straight-chain or cyclic divalent hydrocarbonradical derived by removal of two hydrogen atoms from the same carbonatom of a parent alkane, alkene or alkyne. The divalent radical centerforms a double bond with a single atom on the rest of the molecule.Typical alkylidene radicals include, but are not limited to,ethanylidene; propylidenes such as propan-1-ylidene, propan-2-ylidene,cyclopropan-1-ylidene; butylidenes such as butan-1-ylidene,butan-2-ylidene, 2-methyl-propan-1-ylidene, cyclobutan-1-ylidene; andthe like.

[0041] As used herein, unless otherwise noted, “alkoxy” shall denote anoxygen ether radical of the above-described straight or branched chainalkyl groups. For example, methoxy, ethoxy, n-propoxy, sec-butoxy,t-butoxy, n-hexyloxy and the like.

[0042] As used herein, unless otherwise noted, “cycloalkyl” shall denotea three- to eight-membered, saturated monocyclic carbocyclic ringstructure. Suitable examples include cyclopropyl, cyclobutyl,cyclopentyl, cyclohexyl, cycloheptyl and cyclooctyl. As used herein,unless otherwise noted, “cycloalkenyl” shall denote a three- toeight-membered, partially unsaturated, monocyclic, carbocyclic ringstructure, wherein the ring structure contains at least one double bond.Suitable examples include cyclohexenyl, cyclopentenyl, cycloheptenyl,cyclooctenyl, cyclohex-1,3-dienyl and the like.

[0043] As used herein, unless otherwise noted, “aryl” shall refer tocarbocyclic aromatic groups such as phenyl, naphthyl, and the like.Divalent radicals include phenylene (—C₆H₄—) which is preferablyphen-1,4-diyl, but may also be phen-1,3-diyl.

[0044] As used herein, unless otherwise noted, “aralkyl” shall mean anyalkyl group substituted with an aryl group such as phenyl, naphthyl, andthe like. Examples of aralkyls include benzyl, phenethyl, andphenylpropyl.

[0045] As used herein, unless otherwise noted, “carbocyclyl” shall meanany cyclic group consisting of 3-15 carbon atoms, and preferably 6-9carbon atoms, in the skeleton ring or rings, if the carbocycle is afused or spiro bicyclic or tricyclic group. A carbocycle may besaturated, unsaturated, partially unsaturated, or aromatic. Examplesinclude cycloalkyl, cycloalkenyl, cycloalkynyl; specific examplesinclude phenyl, benzyl, indanyl, and biphenyl. A carbocycle may havesubstituents that are not carbon or hydrogen, such as hydroxy, halo,halomethyl, and so on as provided elsewhere herein.

[0046] As used herein, unless otherwise noted, the terms “heterocycle”,“heterocyclyl” and “heterocyclo” shall denote any three- tofifteen-membered monocyclic, nine- or ten-membered bicyclic or thirteen-or fourteen-membered tricyclic ring structure containing at least oneheteroatom moiety selected from the group consisting of NH, O, SO, SO₂,(C═O), and S, and preferably NH, O, or S, optionally containing one tofour additional heteroatoms in each ring. In some embodiments, theheterocyclyl contains between 1 and 4 or between 1 and 2 additionalheteroatoms. Unless otherwise specified, a heterocyclyl may besaturated, partially unsaturated, aromatic or partially aromatic. Theheterocyclyl group may be attached at any heteroatom or carbon atom thatresults in the creation of a stable structure.

[0047] Exemplary monocyclic heterocyclic groups can includepyrrolidinyl, pyrrolyl, indolyl, pyrazolyl, oxetanyl, pyrazolinyl,imidazolyl, imidazolinyl, imidazolidinyl, oxazolyl, oxazolidinyl,isoxazolinyl, isoxazolyl, thiazaolyl, thiadiazolyl, thiazolidinyl,isothiazolyl, isothiazolidinyl, furyl, tetrahydrofuryl, thienyl,oxadiazolyl, piperidinyl, piperazinyl, 2-oxopiperazinyl,2-oxopiperidinyl, 2-oxopyrrolidinyl, 2-oxazepinyl, azepinyl,hexahydroazepinyl, 4-piperidinyl, pyridyl, N-oxo-pyridyl, pyrazinyl,pyrimidinyl, pyridazinyl, tetrahydropyranyl, tetrahydrothiopyranyl,tetrahydrothiopyranyl sulfone, morpholinyl, thiomorpholinyl,thiomorpholinyl sulfoxide, thiomorpholinyl sulfone, 1,3-dixolane andtetrahydro-1,1-dioxothienyl, dioxanyl, isothiazolidinyl, thietanyl,thiiranyl, triazinyl, triazolyl, tetrazolyl, azatricyclodecanyl,1,4,7,10-tetraoxa-13-aza-cyclopentadecanyl, azetidinyl and the like.

[0048] For example, where Q is a saturated 3-15 membered N-linkedheterocyclyl, Q necessarily contains at least one nitrogen, and thecarbon atoms are sp³ hybridized. Where Q is a fused bicyclicheterocyclyl, the carbon atom of the ring linked to L is sp³ hybridized,provided the adjacent ring (and the common carbon atoms) may be sp²,such as an indanyl where one of the carbon atoms has been replaced withnitrogen.

[0049] In general, exemplary bicyclic heterocyclyls includebenzthiazolyl, benzoxazolyl, benzoxazinyl, benzothienyl, quinuclidinyl,quinolinyl, quinolinyl-N-oxide, tetrahydroisoquinolinyl, isoquinolinyl,benzimidazolyl, benzopyranyl, indolizinyl, benzofuryl, chromonyl,coumarinyl, cinnolinyl, quinoxalinyl, indazolyl, pyrrolopridyl,furopyridinyl (such as furo{2,3-c}pyridinyl, furo{3,1-b}pyridinyl), orfuro{2,3-b}pyridinyl), dihydroisoindolyl, dihydroquinazolinyl (such as3,4-dihydro-4-oxo-quinazolinyl), tetrahydroquinolinyl (such as1,2,3,4-tetrahydroquinolinyl), tetrahydroisoquinolinyl(such as1,2,3,4-tetrahydroisoquiunolinyl), benzisothiazolyl, benzisoxazolyl,benzodiazinyl, benzofurazanyl, benzothiopyranyl, benzotriazolyl,benzpyrazolyl, dihydrobenzofuryl, dihydrobenzothienyl,dihydrobenzothiopyranyl, dihydrobenzothiopyranyl sulfone,dihydrobenzopyranyl, indolinyl, isoindolyl, tetrahydroindoazolyl (suchas 4,5,6,7-tetrahydroindazolyl), isochromanyl, isoindolinyl,naphthyridinyl, phthalazinyl, piperonyl, purinyl, pyridopyridyl,quinazolinyl, tetrahydroquinolinyl, thienofuryl, thienopyridyl,thienothienyl,

[0050] and the like.

[0051] Exemplary tricyclic heterocylclic groups include acridinyl,phenoxazinyl, phenazinyl, phenothiazinyl, carbozolyl, perminidinyl,phenanthrolinyl, carbolinyl, naphthothienyl, thianthrenyl, and the like.

[0052] Preferred heterocyclyl groups include morpholinyl,thiomorpholinyl, piperidinyl, piperazinyl, pyrrolidinyl, pyrimidinyl,pyridyl, pyrrolyl, imidazolyl, oxazolyl, isoxazolyl, acridinyl,azepinyl, hexahydroazepinyl, azatricyclodecanyl,1,4,7,10-tetraoxa-13-aza-cyclopentadecanyl, azetidinyl, indolyl,isoindolyl, thiazolyl, thiadiazolyl, quinolinyl, isoquinolinyl,1,2,3,4-tetrahydroquinolinyl, 1,3,4-trihydroisoquinolinyl,4,5,6,7-tetrahydroindadolyl, benzoxazinyl, benzoaxzolyl, benzthiazolyl,benzimidazolyl, tetrazolyl, oxadiazolyl,

[0053] and

[0054] As used herein, unless otherwise noted, the term“heterocyclyl-alkyl” or “heterocyclyl-alkylene” shall denote any alkylgroup substituted with a heterocyclyl group, wherein theheterocyclyl-alkyl group is bound through the alkyl portion to thecentral part of the molecule. Suitable examples of heterocyclyl-alkylgroups include, but are not limited to piperidinylmethyl,pyrrolidinylmethyl, piperidinylethyl, piperazinylmethyl, pyrrolylbutyl,piperidinylisobutyl, pyridylmethyl, pyrimidylethyl, and the like.

[0055] When a particular group is “substituted” (e.g., alkyl, alkylene,cycloalkyl, aryl, heterocyclyl, heteroaryl), that group may have one ormore substituents, preferably from one to five substituents, morepreferably from one to three substituents, most preferably from one totwo substituents, independently selected from the list of substituents.

[0056] It is intended that the definition of any substituent or variableat a particular location in a molecule be independent of its definitionselsewhere in that molecule. It is understood that substituents andsubstitution patterns on the compounds of this invention can be selectedby one of ordinary skill in the art to provide compounds that arechemically stable and that can be readily synthesized by techniquesknown in the art as well as those methods set forth herein.

[0057] Under standard nomenclature used throughout this disclosure, theterminal portion of the designated side chain is described first,followed by the adjacent functionality toward the point of attachment.Thus, for example, a “phenyl(alkyl)amido(alkyl)” substituent refers to agroup of the formula

[0058] The term “subject” as used herein, refers to an animal,preferably a mammal, most preferably a human, who has been the object oftreatment, observation or experiment.

[0059] The term “therapeutically effective amount” as used herein, meansthat amount of active compound or pharmaceutical agent that elicits thebiological or medicinal response in a tissue system, animal or humanthat is being sought by a researcher, veterinarian, medical doctor orother clinician, which includes prevention, inhibition of onset, oralleviation of the symptoms of the disease or disorder being treated.

[0060] As used herein, the term “composition” is intended to encompass aproduct comprising the specified ingredients in the specified amounts,as well as any product which results, directly or indirectly, fromcombinations of the specified ingredients in the specified amounts.

[0061] Abbreviations used in the specification, particularly in theSchemes and Examples, are as follows: DBAD = Di-tert-butylazodicarboxylate DCE = 1,2-dichloroethane DCM = Dichloromethane DEAD =Diethyl azodicarboxylate DMA = N,N-dimethylacetamide DMAP =4-N,N-dimethylamino- pyridine DME = 1,2-dimethoxyethane DMF =Dimethylformamide DMSO = Dimethylsulfoxide RT = Room temperature TEA =Triethylamine TFA = Trifluoroacetic acid THF = Tetrahydrofuran

[0062] B. Compounds The invention features a compound of formula (I):

[0063] wherein

[0064] L is a direct bond, or an optionally C₁₋₄alkyl substitutedradical selected from the group consisting of C₁₋₄alkylene orC₃₋₄alkenylene wherein NR¹R² is attached to an sp³ hybridized carbon,C₃₋₄alkynylene wherein NR¹R² is attached to an sp³ hybridized carbon,C₂₋₄alkylidene wherein NR¹R² is attached to an sp³ hybridized carbon,aryloxy wherein NR¹NR² is not attached to the oxygen, arylthio whereinNR¹R² is not attached to the sulfur, C₂₋₄alkoxy wherein NR¹R² is notattached to the oxygen or a carbon attached to the oxygen, C₂₋₄alkylthiowherein NR¹R² is not attached to the sulfur or a carbon attached to thesulfur, and —C₂₋₃alkyl-X—C₁₋₂alkyl- wherein X is O, S or NH and whereinNR¹R² is not attached to a carbon attached to X;

[0065] p is 0, 1 or 2;

[0066] q is 1 or 2; provided that 2<p+q<4;

[0067] R¹ and R² are independently selected from hydrogen, C₁₋₃ alkyl,allyl, C₃₋₈ cycloalkyl, 5-9 membered heterocyclyl, phenyl, and(phenyl)C₁₋₃ alkylene, or taken together with the nitrogen to which theyare attached, they form a non-aromatic 4-13 membered heterocyclyloptionally including up to two additional heteroatoms independentlyselected from O, S, and NH; and wherein R¹ and R² are optionally andindependently substituted with substitutents selected from the groupconsisting of trifluoromethyl, halo, nitro, cyano, hydroxy, and C₁₋₃alkyl;

[0068] one of R³, R⁴ and R⁵ is G and the other two independently arehydrogen, fluoro, chloro, bromo, nitro, trifluoromethyl, methyl, or C₁₋₃alkoxy;

[0069] G is L²Q;

[0070] L² is unbranched —(CH₂)_(n)— wherein n is an integer from 1 to 7(preferably n is 1 to 4, more preferably n is 1);

[0071] Q is NR⁸R⁹ wherein R⁸ is independently selected from hydrogen,C₁₋₆ alkyl, C₃₋₆ alkenyl, C₄₋₉ carbocyclyl, 3-12 membered heterocyclyl(preferably 5-9 or 5-8-membered heterocyclyl), phenyl, (5-9-memberedheterocyclyl)C₁₋₆ alkylene, and (phenyl)C₁₋₆ alkylene; and R⁹ isindependently selected from C₁₋₆ alkyl, C₃₋₆ alkenyl, C₄₋₉ memberedcarbocyclyl, 3-12 membered heterocyclyl (preferably 5-9 or 5-8-memberedheterocyclyl), phenyl, (5-9-membered heterocyclyl)C₁₋₆ alkylene, and(phenyl)C₁₋₆ alkylene; or Q is a saturated 3-15 membered N-linkedheterocyclyl, wherein, in addition to the N-linking nitrogen, the 3-15membered heterocyclyl may optionally contain between 1 and 4 additionalheteroatoms independently selected from O, S, and NH;

[0072] and wherein Q is optionally substituted with 1-3 substituentsselected (in addition to the preceding paragraph) from the groupconsisting of tert-butyloxycarbonyl, hydroxy, halo, nitro, amino, cyano,carboxamide, C₁₋₆ alkyl, C₁₋₆ acyl, 5-9-membered heterocyclyl, —N(C₁₋₆alkyl)(5-9 membered heterocyclyl), —NH(5-9 membered heterocyclyl),—O(5-9 membered heterocyclyl), (5-9 membered heterocyclyl)C₁₋₃ alkylene,C₁₋₂-hydroxyalkylene, C₁₋₆ alkoxy, (C₃₋₆ cycloalkyl)-O—, phenyl,(phenyl)C₁₋₃ alkylene, and (phenyl)C₁₋₃ alkylene-O—; and where saidsubstituent groups of Q may optionally have between 1 and 3 substituentsindependently selected from trifluoromethyl, halo, nitro, cyano,hydroxy, and C₁₋₃ alkyl;

[0073] R^(a) are independently C₁₋₃ alkyl, triflouromethyl;

[0074] m is 0, 1, 2 or 3; and

[0075] wherein each of the above alkyl, alkylene, alkenyl, heterocyclyl,cycloalkyl, carbocyclyl, and aryl groups may each be independently andoptionally substituted with between 1 and 3 substituents independentlyselected from methoxy, halo, amino, nitro, hydroxyl, and C₁₋₃ alkyl;

[0076] or a pharmaceutically acceptable salt, ester, tautomer, solvateor amide thereof.

[0077] The invention features compounds of formula (I). Preferredcompounds include those wherein:

[0078] (a) NR¹R² taken together form substituted or unsubstitutedmorpholinyl, thiomorpholinyl, piperidinyl, methylpiperidinyl,piperazinyl, N-methylpiperazinyl, dimethylamino, pyrrolidinyl,azatricyclodecanyl, cyclohexylmethylamino, methylphenethylamino,pyridylamino, anilino, diethylamino, methylethylamino, ethylpropylamino,or dipropylamino;

[0079] (b) NR¹R² taken together form a saturated N-linkednitrogen-containing heterocyclyl;

[0080] (c) NR¹R² taken together form a substituent selected fromsubstituted or unsubstituted piperidinyl, substituted or unsubstitutedpiperazinyl, pyrrolinyl, pyrrolidinyl, thiomorpholinyl, and morpholinyl;

[0081] (d) NR¹R² taken together form a substituent selected from N-(C₁₋₆alkyl)piperazinyl, N-phenyl-piperazinyl, 1,3,8-triaza-spiro{4.5}decyl,and 1,4-dioxa-8-aza-spiro{4.5}decyl;

[0082] (e) NR¹R² taken together form a monovalent radical of an amineselected from aziridine, 1,4,7-trioxa-10-aza-cyclododecane,thiazolidine, 1-phenyl-1,3,8-triaza-spiro{4.5}decan-4-one,piperidine-3-carboxylic acid diethylamide,1,2,3,4,5,6-hexahydro-{2,3′}bipyridinyl,4-(3-trifluoromethyl-phenyl)-piperazine, 2-piperazin-1-yl-pyrimidine,piperidine-4-carboxylic acid amide, methyl-(2-pyridin-2-yl-ethyl)-amine,{2-(3,4-dimethoxy-phenyl)-ethyl}-methyl-amine, thiomorpholinyl,allyl-cyclopentyl-amine, {2-(1H-indol-3-yl)-ethyl}-methyl-amine,1-piperidin-4-yl-1,3-dihydro-benzoimidazol-2-one,2-(piperidin-4-yloxy)-pyrimidine, piperidin-4-yl-pyridin-2-yl-amine,phenylamine, pyridin-2-ylamine;

[0083] (f) NR¹R² taken together form a substituent selected from thegroup consisting of morpholinyl and piperidinyl, wherein saidsubstituent is optionally substituted with between 1 and 3 substituentsselected from hydroxy, halo, carboxamide, C₁₋₆ alkyl, C₁₋₆ acyl, 5-9membered heterocyclyl, —N(C₁₋₆ alkyl)(5-9 membered heterocyclyl),—NH(5-9 membered heterocyclyl), —O(5-9 membered heterocyclyl), (5-9membered heterocyclyl)C₁₋₃ alkylene, C₁₋₂-hydroxyalkylene, C₁₋₆ alkoxy,(C₃₋₆ cycloalkyl)-O—, phenyl, (phenyl)C₁₋₃ alkylene, and (phenyl)C₁₋₃alkylene-O— where each of above heterocyclyl, phenyl, and alkyl groupsmay be optionally substituted with from 1 to 3 substituentsindependently selected from trifluoromethyl, halo, nitro, cyano,hydroxy, and C₁₋₃ alkyl;

[0084] (g) NR¹R² taken together form a saturated N-linkednitrogen-containing heterocyclyl substituted with a substituent selectedfrom the group consisting of pyridyl, pyrimidyl, furyl, thiofuryl,imidazolyl, (imidazolyl)C₁₋₆ alkylene, oxazolyl, thiazolyl,2,3-dihydro-indolyl, benzimidazolyl, 2-oxobenzimidazolyl,(tetrazolyl)C₁₋₆ alkylene, tetrazolyl, (triazolyl)C₁₋₆ alkylene,triazolyl, (pyrrolyl)C₁₋₆ alkylene, pyrrolidinyl, and pyrrolyl;

[0085] (h) NR¹R² taken together form morpholinyl, piperidinyl,pyrrolidinyl, or diethylamino;

[0086] (i) NR¹R² taken together form morpholinyl, piperidinyl, orpyrrolidinyl;

[0087] (j) NR¹R² taken together form morpholinyl;

[0088] (k) one of R³ and R⁴ is G;

[0089] (l) R³ is G;

[0090] (m) R⁴ is G;

[0091] (n) q is 2 and p is 1;

[0092] (O) q is 1 and p is 1;

[0093] (p) q is 2 and p is 2;

[0094] (q) L is —CH₂—;

[0095] (r) L is a direct bond;

[0096] (s) L is —CH₂CH₂—;

[0097] (t) L² is —CH₂—;

[0098] (u) Q is selected from substituted or unsubstituted pyrrolidinyl,piperidinyl, methylpiperidinyl, morpholinyl, thiomorpholinyl,azatricyclodecanyl, cyclohexylamino, cyclohexylmethylamino, piperazinyl,N-methylpiperazinyl, dimethylamino, methylphenethylamino, pyridylamino,anilino, diethylamino, methylethylamino, ethylpropylamino,dipropylamino, or 1,4,7,10-tetraoxa-13-aza-cyclopentadecanyl;

[0099] (v) Q is a saturated N-linked nitrogen-containing heterocyclyl;

[0100] (w) Q is selected from substituted or unsubstituted piperidinyl,substituted or unsubstituted piperazinyl, pyrrolinyl, pyrrolidinyl,thiomorpholinyl, and morpholinyl;

[0101] (x) substituted Q are selected from N-(C₁₋₆ alkyl)piperazinyl,N-phenyl-piperazinyl, 1,3,8-triaza-spiro{4.5}decyl, and1,4-dioxa-8-aza-spiro{4.5}decyl;

[0102] (y) Q is a monovalent radical of an amine selected fromaziridine, 1,4,7-trioxa-10-aza-cyclododecane, thiazolidine,1-phenyl-1,3,8-triaza-spiro{4.5}decan-4-one, piperidine-3-carboxylicacid diethylamide, 1,2,3,4,5,6-hexahydro-{2,3′}bipyridinyl,4-(3-trifluoromethyl-phenyl)-piperazine, 2-piperazin-1-yl-pyrimidine,piperidine-4-carboxylic acid amide, methyl-(2-pyridin-2-yl-ethyl)-amine,{2-(3,4-dimethoxy-phenyl)-ethyl}-methyl-amine, thiomorpholinyl,allyl-cyclopentyl-amine, {2-(1H-indol-3-yl)-ethyl}-methyl-amine,1-piperidin-4-yl-1,3-dihydro-benzoimidazol-2-one,2-(piperidin-4-yloxy)-pyrimidine, piperidin-4-yl-pyridin-2-yl-amine,phenylamine, and pyridin-2-ylamine;

[0103] (z) Q is selected from morpholinyl, pyridyl and piperidinyl,optionally substituted with between 1 and 3 substituents independentlyselected from hydroxy, halo, carboxamide, C₁₋₆ alkyl, C₁₋₆ acyl, 5-9membered or 6-9 membered heterocyclyl, —N(C₁₋₆ alkyl)(5-9 membered or6-9 membered heterocyclyl), —NH(5-9 membered or 6-9 memberedheterocyclyl), —O(5-9 or 6-9 membered heterocyclyl), (5-9 membered or6-9 membered heterocyclyl)C₁₋₃ alkylene, C₁₋₂-hydroxyalkylene, C₁₋₆alkoxy, (C₃₋₆ cycloalkyl)-O—, phenyl, (phenyl)C₁₋₃ alkylene, and(phenyl)C₁₋₃ alkylene-O— where each of above heterocyclyl, phenyl, andalkyl groups may be optionally substituted with from 1 to 3 substituentsindependently selected from trifluoromethyl, halo, nitro, cyano,hydroxy, and C₁₋₃ alkyl;

[0104] (aa) Q is substituted with a substituent comprising a 5-9membered or 6-9 membered heterocyclyl group selected from: pyridyl,pyrimidyl, furyl, thiofuryl, imidazolyl, (imidazolyl)C₁₋₆ alkylene,oxazolyl, thiazolyl, 2,3-dihydro-indolyl, benzimidazolyl,2-oxobenzimidazolyl, (tetrazolyl)C₁₋₆ alkylene, tetrazolyl,(triazolyl)C₁₋₆ alkylene, triazolyl, (pyrrolyl)C₁₋₆ alkylene,pyrrolidinyl, and pyrrolyl;

[0105] (bb) Q is morpholinyl, piperidinyl, pyrrolidinyl, ordiethylamino;

[0106] (cc) Q is morpholinyl, piperidinyl, or pyrrolidinyl;

[0107] (dd) R⁸ is hydrogen;

[0108] (ee) R⁹ is C₁₋₆ alkyl;

[0109] (ff) R⁹ is cyclohexyl;

[0110] (gg) R⁸ and R⁹ independently are C₁₋₆ alkyl;

[0111] (hh) R⁸ and R⁹ are methyl;

[0112] (ii) R⁸ and R⁹ are ethyl;

[0113] (jj) R⁹ is selected from phenyl or 5-9 membered aromaticheterocyclyl, wherein said phenyl or aromatic heterocyclyl is optionallysubstituted with 1-3 substituents selected from hydroxy, halo, nitro,cyano, trifluoromethyl, and C₁₋₃ alkyl;

[0114] (kk) R⁹ is selected from substituted or unsubstituted phenyl,pyridyl, pyrimidyl, furyl, thiofuryl, imidazolyl, (imidazolyl)C₁₋₆alkylene, oxazolyl, thiazolyl, 2,3-dihydro-indolyl, benzimidazolyl,2-oxobenzimidazolyl, (tetrazolyl)C₁₋₆ alkylene, tetrazolyl,(triazolyl)C₁₋₆ alkylene, triazolyl, (pyrrolyl)C₁₋₆ alkylene, andpyrrolyl;

[0115] (ll) R⁹ is substituted or unsubstituted phenyl;

[0116] (mm) R⁹ is substituted or unsubstituted pyridyl;

[0117] (nn) wherein R¹ and R² are independently selected from C₂ alkyl,or taken together with the nitrogen to which they are attached, theyform a non-aromatic 5-6 membered heterocyclyl optionally including anadditional heteroatom independently selected from O, S, and NH; one ofR³, R⁴, and R⁵ is G and the two remaining are H; G is L²Q; L² ismethylene; Q is NR¹R⁹ wherein R⁸ is independently selected fromhydrogen, C₁₋₂ alkyl, C₃ alkenyl, C₅₋₉ carbocyclyl, 3-12 memberedheterocyclyl (preferably 5-9 or 6-9), phenyl, (5-9-memberedheterocyclyl)C₂ alkylene, and (phenyl)C₂ alkylene; and R⁹ isindependently selected from C₁₋₂ alkyl, C₃ alkenyl, C₅₋₉ carbocyclyl,3-12 membered heterocyclyl (for example, 5-9 membered or 6-9 memberedheterocyclyl, and in some cases preferably 6-membered), phenyl,(5-9-membered heterocyclyl)C₁₋₆ alkylene, and (phenyl)C₁₋₆ alkylene; orQ is a saturated 3-15 membered N-linked heterocyclyl (preferably 5-9 or6-9), wherein, in addition to the N-linking nitrogen, the 3-15 memberedheterocyclyl may optionally contain between 1 and 4 additionalheteroatoms independently selected from O, S, and NH; wherein each ofthe above alkyl, alkylene, alkenyl, alkenylene, heterocyclyl,cycloalkyl, and aryl groups may each be independently and optionallysubstituted with substituents selected from tert-butyloxycarbonyl,hydroxy, halo, nitro, amino, cyano, carboxamide, 6-9-memberedheterocyclyl, —NH(6-membered heterocyclyl), —O(6-membered heterocyclyl),C₁₋₂ hydroxyalkylene, C₁₋₂ alkoxy, phenyl, and benzyl, and where each ofabove heterocyclyl, phenyl, and alkyl substituent groups of Q may beoptionally substituted with trifluoromethyl; or a pharmaceuticallyacceptable salt, ester, tautomer, solvate or amide thereof;

[0118] (oo) (1) NR¹R² taken together form morpholinyl, piperidinyl,pyrrolidinyl, or diethylamino, and (2) Q is selected from substituted orunsubstituted piperidinyl, piperazinyl, pyrrolinyl, pyrrolidinyl,thiomorpholinyl, and morpholinyl;

[0119] (pp) (1) NR¹R² taken together form piperidinyl or pyrrolidinyl,(2) n is 1, and (3) Q is selected from morpholinyl and piperidinyl;

[0120] (qq) Q is piperidinyl or substituted piperidinyl;

[0121] (rr) NR¹R² taken together form piperidinyl, pyrrolidinyl, ordiethylamino, n is 1, and wherein Q is NR⁸R⁹ and R⁸ is H and R⁹ isselected from phenyl or aromatic 5-9 membered heterocyclyl, wherein saidphenyl or heterocyclyl is optionally substituted with 1-3 substituentsselected from trifluoromethyl, halo, nitro, cyano, hydroxy, and C₁₋₃alkyl;

[0122] (ss) R^(a) is hydrogen; or

[0123] (tt) combinations of (a) through (ss) above.

[0124] Examples of compounds of the invention include:

[0125] 4-{2-(4-Piperidin-1-ylmethyl-piperidin-1-yl)-benzyl}-morpholine;

[0126]Cyclohexyl-{1-(4-pyrrolidin-1-ylmethyl-phenyl)-piperidin-4-ylmethyl}-amine;

[0127]1-{1-(4-Pyrrolidin-1-ylmethyl-phenyl)-piperidin-4-ylmethyl}-azacyclotridecane;

[0128]Diethyl-{1-(4-pyrrolidin-1-ylmethyl-phenyl)-piperidin-4-ylmethyl}-amine;

[0129] Dimethyl-{1-(4-pyrrolidin-1-ylmethyl-phenyl)-piperidin-4-ylmethyl}-amine;

[0130]1-Methyl-4-{1-(4-pyrrolidin-1-ylmethyl-phenyl)-piperidin-4-ylmethyl}-piperazine;

[0131]1-{1-(4-Pyrrolidin-1-ylmethyl-phenyl)-piperidin-4-ylmethyl}-piperidin-4-ol;

[0132]4-{1-(4-Pyrrolidin-1-ylmethyl-phenyl)-piperidin-4-ylmethyl}-thiomorpholine;

[0133]1-{1-(4-Pyrrolidin-1-ylmethyl-phenyl)-piperidin-4-ylmethyl}-piperidine;

[0134]4-{1-(4-Pyrrolidin-1-ylmethyl-phenyl)-piperidin-4-ylmethyl}-morpholine;

[0135]4-{3-(4-Pyrrolidin-1-ylmethyl-piperidin-1-yl)-benzyl}-thiomorpholine;

[0136] 4-{3-(4-Pyrrolidin-1-ylmethyl-piperidin-1-yl)-benzyl}-morpholine;

[0137]4-Pyrrolidin-1-ylmethyl-1-(3-pyrrolidin-1-ylmethyl-phenyl)-piperidine;

[0138] 1-{3-(4-Pyrrolidin-1-ylmethyl-piperidin-1-yl)-benzyl}-piperidine;

[0139]1-{4-(4-Pyrrolidin-1-ylmethyl-piperidin-1-yl)-benzyl}-azacyclotridecane;

[0140]Cyclohexyl-{4-(4-pyrrolidin-1-ylmethyl-piperidin-1-yl)-benzyl}-amine;

[0141]1-{4-(4-Pyrrolidin-1-ylmethyl-piperidin-1-yl)-benzyl}-piperidin-4-ol;

[0142]1-Methyl-4-{4-(4-pyrrolidin-1-ylmethyl-piperidin-1-yl)-benzyl}-piperazine;

[0143]4-{4-(4-Pyrrolidin-1-ylmethyl-piperidin-1-yl)-benzyl}-thiomorpholine;

[0144] 4-{4-(4-Pyrrolidin-1-ylmethyl-piperidin-1-yl)-benzyl}-morpholine;

[0145]Dimethyl-{4-(4-pyrrolidin-1-ylmethyl-piperidin-1-yl)-benzyl}-amine;

[0146] 4-{2-(4-Pyrrolidin-1-ylmethyl-piperidin-1-yl)-benzyl}-morpholine;

[0147]4-{1-(4-Piperidin-1-ylmethyl-phenyl)-piperidin-4-ylmethyl}-morpholine;

[0148] 1-{4-(4-Pyrrolidin-1-ylmethyl-piperidin-1-yl)-benzyl}-piperidine;

[0149]Cyclohexyl-{1-(4-morpholin-4-ylmethyl-phenyl)-piperidin-4-yl}-amine;

[0150]Cyclohexyl-methyl-{1-(4-morpholin-4-ylmethyl-phenyl)-piperidin-4-yl}-amine;

[0151]4-{4-{4-(4-Methyl-piperazin-1-yl)-piperidin-1-yl}-benzyl}-morpholine;

[0152]Ethyl-methyl-{1-(4-morpholin-4-ylmethyl-phenyl)-piperidin-4-yl}-amine;

[0153] 4-{1-(4-Morpholin-4-ylmethyl-phenyl)-piperidin-4-yl}-morpholine;

[0154] 4-{4-(4-Pyrrolidin-1-yl-piperidin-1-yl)-benzyl}-morpholine;

[0155] 1′-(4-Morpholin-4-ylmethyl-phenyl)-{1,4′}bipiperidinyl;

[0156] 1′-(4-Piperidin-1-ylmethyl-phenyl)-{1,4′}bipiperidinyl;

[0157] (4-{1,4′}Bipiperidinyl-1′-yl-benzyl)-pyridin-2-yl-amine;

[0158]Phenyl-{1-(4-pyrrolidin-1-ylmethyl-phenyl)-piperidin-4-ylmethyl}-amine;

[0159]Pyridin-2-yl-{1-(4-pyrrolidin-1-ylmethyl-phenyl)-piperidin-4-ylmethyl}-amine;

[0160]1-{1-(4-Piperidin-1-ylmethyl-phenyl)-piperidin-4-ylmethyl}-piperidine;

[0161]4-Pyrrolidin-1-ylmethyl-1-(4-pyrrolidin-1-ylmethyl-phenyl)-piperidine;

[0162](4-Fluoro-phenyl)-{4-(4-pyrrolidin-1-ylmethyl-piperidin-1-yl)-benzyl}-amine;

[0163]4-{2-{1-(4-Piperidin-1-ylmethyl-phenyl)-pyrrolidin-3-yl}-ethyl}-morpholine;

[0164]Diethyl-{2-{1-(4-piperidin-1-ylmethyl-phenyl)-pyrrolidin-3-yl}-ethyl}-amine;

[0165]Methyl-phenethyl-{2-{1-(4-piperidin-1-ylmethyl-phenyl)-pyrrolidin-3-yl}-ethyl}-amine;

[0166]1-[4-(4-Pyrrolidin-1-ylmethyl-piperidin-1-yl)-3-trifluoromethyl-benzyl]-piperidine;

[0167]1-(2-Nitro-4-pyrrolidin-1-ylmethyl-phenyl)-4-pyrrolidin-1-ylmethyl-piperidine;

[0168]4-[3-Nitro-4-(4-pyrrolidin-1-ylmethyl-piperidin-1-yl)-benzyl]-morpholine;

[0169]1-[3-Nitro-4-(4-pyrrolidin-1-ylmethyl-piperidin-1-yl)-benzyl]-piperidin-4-ol;

[0170]1-[4-(4-Pyrrolidin-1-ylmethyl-piperidin-1-yl)-2-trifluoromethyl-benzyl]-piperidine;

[0171]1-Isopropyl-4-[3-methyl-4-(4-pyrrolidin-1-ylmethyl-piperidin-1-yl)-benzyl]-piperazine;

[0172]1-(2-Methyl-4-pyrrolidin-1-ylmethyl-phenyl)-4-pyrrolidin-1-ylmethyl-pyrrolidine;

[0173]1-[3-Methyl-4-(4-pyrrolidin-1-ylmethyl-piperidin-1-yl)-benzyl]-pyrrolidine;

[0174]1-{1-[4-(4-Pyrrolidin-1-yl-piperidin-1-ylmethyl)-2-trifluoromethyl-phenyl]-piperidin-4-ylmethyl}-pyrrolidine;

[0175]1-(1-{3-Trifluoromethyl-4-[4-(4-trifluoromethyl-phenyl)-piperidin-1-ylmethyl]-phenyl}-piperidin-4-ylmethyl)-pyrrolidine;

[0176]1-{1-[2-Fluoro-4-(4-phenyl-piperidin-1-ylmethyl)-phenyl]-piperidin-4-ylmethyl}-pyrrolidine;

[0177][3-Fluoro-4-(4-pyrrolidin-1-ylmethyl-piperidin-1-yl)-benzyl]-dimethyl-amine;

[0178]1-[3-Fluoro-4-(4-pyrrolidin-1-ylmethyl-piperidin-1-yl)-benzyl]-piperidine;

[0179]13-[4-(4-Pyrrolidin-1-ylmethyl-piperidin-1-yl)-2-trifluoromethyl-benzyl]-1,4,7,10-tetraoxa-13-aza-cyclopentadecaneditrifluoromethanesulfonate; and

[0180]{1-[4-(4-Pyrrolidin-1-ylmethyl-piperidin-1-yl)-3-trifluoromethyl-benzyl]-piperidin-4-yl}-methanol.

[0181] Preferred example compounds include:

[0182] (4-{1,4′}Bipiperidinyl-1′-yl-benzyl)-pyridin-2-yl-amine;

[0183] 1′-(4-Morpholin-4-ylmethyl-phenyl)-{1,4′}bipiperidinyl;

[0184] 1′-(4-Piperidin-1-ylmethyl-phenyl)-{1,4′}bipiperidinyl;

[0185]1-{1-(4-Piperidin-1-ylmethyl-phenyl)-piperidin-4-ylmethyl}-piperidine;

[0186]4-{1-(4-Piperidin-1-ylmethyl-phenyl)-piperidin-4-ylmethyl}-morpholine;

[0187]1-{1-(4-Pyrrolidin-1-ylmethyl-phenyl)-piperidin-4-ylmethyl}-piperidin-4-ol;

[0188]1-{1-(4-Pyrrolidin-1-ylmethyl-phenyl)-piperidin-4-ylmethyl}-piperidine;

[0189] 1-{3-(4-Pyrrolidin-1-ylmethyl-piperidin-1-yl)-benzyl}-piperidine;

[0190]1-{4-(4-Pyrrolidin-1-ylmethyl-piperidin-1-yl)-benzyl}-azacyclotridecane;

[0191]1-{4-(4-Pyrrolidin-1-ylmethyl-piperidin-1-yl)-benzyl}-piperidin-4-ol;

[0192] 1-{4-(4-Pyrrolidin-1-ylmethyl-piperidin-1-yl)-benzyl}-piperidine;

[0193]1-Methyl-4-{1-(4-pyrrolidin-1-ylmethyl-phenyl)-piperidin-4-ylmethyl}-piperazine;

[0194]1-Methyl-4-{4-(4-pyrrolidin-1-ylmethyl-piperidin-1-yl)-benzyl}-piperazine;

[0195]4-{1-(4-Pyrrolidin-1-ylmethyl-phenyl)-piperidin-4-ylmethyl}-morpholine;

[0196]4-{1-(4-Pyrrolidin-1-ylmethyl-phenyl)-piperidin-4-ylmethyl}-thiomorpholine;

[0197]4-{3-(4-Pyrrolidin-1-ylmethyl-piperidin-1-yl)-benzyl}-thiomorpholine;

[0198]4-{4-(4-Pyrrolidin-1-ylmethyl-piperidin-1-yl)-benzyl}-thiomorpholine;

[0199]4-{2-{1-(4-Piperidin-1-ylmethyl-phenyl)-pyrrolidin-3-yl}-ethyl}-morpholine;

[0200]4-Pyrrolidin-1-ylmethyl-1-(3-pyrrolidin-1-ylmethyl-phenyl)-piperidine;

[0201]4-Pyrrolidin-1-ylmethyl-1-(4-pyrrolidin-1-ylmethyl-phenyl)-piperidine;

[0202]Cyclohexyl-{1-(4-pyrrolidin-1-ylmethyl-phenyl)-piperidin-4-ylmethyl}-amine;

[0203]Cyclohexyl-{4-(4-pyrrolidin-1-ylmethyl-piperidin-1-yl)-benzyl}-amine;

[0204]Cyclohexyl-methyl-{1-(4-morpholin-4-ylmethyl-phenyl)-piperidin-4-yl}-amine;

[0205]Diethyl-{1-(4-pyrrolidin-1-ylmethyl-phenyl)-piperidin-4-ylmethyl}-amine;

[0206]Diethyl-{2-{1-(4-piperidin-1-ylmethyl-phenyl)-pyrrolidin-3-yl}-ethyl}-amine;

[0207]Dimethyl-{1-(4-pyrrolidin-1-ylmethyl-phenyl)-piperidin-4-ylmethyl}-amine;

[0208]Dimethyl-{4-(4-pyrrolidin-1-ylmethyl-piperidin-1-yl)-benzyl}-amine;

[0209]Methyl-phenethyl-{2-{1-(4-piperidin-1-ylmethyl-phenyl)-pyrrolidin-3-yl}-ethyl}-amine;

[0210]Phenyl-{1-(4-pyrrolidin-1-ylmethyl-phenyl)-piperidin-4-ylmethyl}-amine;

[0211]Pyridin-2-yl-{1-(4-pyrrolidin-1-ylmethyl-phenyl)-piperidin-4-ylmethyl}-amine;

[0212]1-(2-Nitro-4-pyrrolidin-1-ylmethyl-phenyl)-4-pyrrolidin-1-ylmethyl-piperidine;

[0213]1-[3-Nitro-4-(4-pyrrolidin-1-ylmethyl-piperidin-1-yl)-benzyl]-piperidin-4-ol;

[0214]1-[4-(4-Pyrrolidin-1-ylmethyl-piperidin-1-yl)-2-trifluoromethyl-benzyl]-piperidine;

[0215]1-(2-Methyl-4-pyrrolidin-1-ylmethyl-phenyl)-4-pyrrolidin-1-ylmethyl-pyrrolidine;

[0216]1-[3-Methyl-4-(4-pyrrolidin-1-ylmethyl-piperidin-1-yl)-benzyl]-pyrrolidine;

[0217]1-{1-[4-(4-Pyrrolidin-1-yl-piperidin-1-ylmethyl)-2-trifluoromethyl-phenyl]-piperidin-4-ylmethyl}-pyrrolidine;

[0218]1-{1-[2-Fluoro-4-(4-phenyl-piperidin-1-ylmethyl)-phenyl]-piperidin-4-ylmethyl}-pyrrolidine;

[0219][3-Fluoro-4-(4-pyrrolidin-1-ylmethyl-piperidin-1-yl)-benzyl]-dimethyl-amine;and

[0220]1-[3-Fluoro-4-(4-pyrrolidin-1-ylmethyl-piperidin-1-yl)-benzyl]-piperidine.

[0221] More preferred example compounds include:

[0222] 1′-(4-Piperidin-1-ylmethyl-phenyl)-{1,4′}bipiperidinyl;

[0223]1-{1-(4-Piperidin-1-ylmethyl-phenyl)-piperidin-4-ylmethyl}-piperidine;

[0224]4-{1-(4-Piperidin-1-ylmethyl-phenyl)-piperidin-4-ylmethyl}-morpholine;

[0225]1-{1-(4-Pyrrolidin-1-ylmethyl-phenyl)-piperidin-4-ylmethyl}-piperidin-4-ol;

[0226]1-{1-(4-Pyrrolidin-1-ylmethyl-phenyl)-piperidin-4-ylmethyl}-piperidine;

[0227]1-{4-(4-Pyrrolidin-1-ylmethyl-piperidin-1-yl)-benzyl}-piperidin-4-ol;

[0228] 1-{4-(4-Pyrrolidin-1-ylmethyl-piperidin-1-yl)-benzyl}-piperidine;

[0229]1-Methyl-4-{1-(4-pyrrolidin-1-ylmethyl-phenyl)-piperidin-4-ylmethyl}-piperazine;

[0230]4-{1-(4-Pyrrolidin-1-ylmethyl-phenyl)-piperidin-4-ylmethyl}-morpholine;

[0231]4-{1-(4-Pyrrolidin-1-ylmethyl-phenyl)-piperidin-4-ylmethyl}-thiomorpholine;

[0232]4-{4-(4-Pyrrolidin-1-ylmethyl-piperidin-1-yl)-benzyl}-thiomorpholine;

[0233]4-{2-{1-(4-Piperidin-1-ylmethyl-phenyl)-pyrrolidin-3-yl}-ethyl}-morpholine;

[0234]4-Pyrrolidin-1-ylmethyl-1-(4-pyrrolidin-1-ylmethyl-phenyl)-piperidine;

[0235]Cyclohexyl-{1-(4-pyrrolidin-1-ylmethyl-phenyl)-piperidin-4-ylmethyl}-amine;

[0236]Cyclohexyl-{4-(4-pyrrolidin-1-ylmethyl-piperidin-1-yl)-benzyl}-amine;

[0237]Diethyl-{1-(4-pyrrolidin-1-ylmethyl-phenyl)-piperidin-4-ylmethyl}-amine;

[0238]Diethyl-{2-{1-(4-piperidin-1-ylmethyl-phenyl)-pyrrolidin-3-yl}-ethyl}-amine;

[0239]Dimethyl-{1-(4-pyrrolidin-1-ylmethyl-phenyl)-piperidin-4-ylmethyl}-amine;

[0240]Dimethyl-{4-(4-pyrrolidin-1-ylmethyl-piperidin-1-yl)-benzyl}-amine;

[0241]Methyl-phenethyl-{2-{1-(4-piperidin-1-ylmethyl-phenyl)-pyrrolidin-3-yl}-ethyl}-amine;

[0242]Pyridin-2-yl-{1-(4-pyrrolidin-1-ylmethyl-phenyl)-piperidin-4-ylmethyl}-amine;

[0243]1-(2-Nitro-4-pyrrolidin-1-ylmethyl-phenyl)-4-pyrrolidin-1-ylmethyl-piperidine;

[0244]1-[3-Nitro-4-(4-pyrrolidin-1-ylmethyl-piperidin-1-yl)-benzyl]-piperidin-4-ol;

[0245]1-(2-Methyl-4-pyrrolidin-1-ylmethyl-phenyl)-4-pyrrolidin-1-ylmethyl-pyrrolidine;

[0246][3-Fluoro-4-(4-pyrrolidin-1-ylmethyl-piperidin-1-yl)-benzyl]-dimethyl-amine;and

[0247]1-[3-Fluoro-4-(4-pyrrolidin-1-ylmethyl-piperidin-1-yl)-benzyl]-piperidine.

[0248] Even more preferred example compounds include:

[0249]1-{1-(4-Pyrrolidin-1-ylmethyl-phenyl)-piperidin-4-ylmethyl}-piperidin-4-ol;

[0250]1-{1-(4-Pyrrolidin-1-ylmethyl-phenyl)-piperidin-4-ylmethyl}-piperidine;

[0251]1-Methyl-4-{1-(4-pyrrolidin-1-ylmethyl-phenyl)-piperidin-4-ylmethyl}-piperazine;

[0252] 1-{4-(4-Pyrrolidin-1-ylmethyl-piperidin-1-yl)-benzyl}-piperidine;

[0253]4-{1-(4-Pyrrolidin-1-ylmethyl-phenyl)-piperidin-4-ylmethyl}-morpholine;

[0254]4-{1-(4-Pyrrolidin-1-ylmethyl-phenyl)-piperidin-4-ylmethyl}-thiomorpholine;

[0255]4-{2-{1-(4-Piperidin-1-ylmethyl-phenyl)-pyrrolidin-3-yl}-ethyl}-morpholine;

[0256]4-Pyrrolidin-1-ylmethyl-1-(4-pyrrolidin-1-ylmethyl-phenyl)-piperidine;

[0257]Cyclohexyl-{1-(4-pyrrolidin-1-ylmethyl-phenyl)-piperidin-4-ylmethyl}-amine;

[0258]Cyclohexyl-{4-(4-pyrrolidin-1-ylmethyl-piperidin-1-yl)-benzyl}-amine;

[0259]Diethyl-{1-(4-pyrrolidin-1-ylmethyl-phenyl)-piperidin-4-ylmethyl}-amine;

[0260]Diethyl-{2-{1-(4-piperidin-1-ylmethyl-phenyl)-pyrrolidin-3-yl}-ethyl}-amine;

[0261]Dimethyl-{1-(4-pyrrolidin-1-ylmethyl-phenyl)-piperidin-4-ylmethyl}-amine;

[0262]Methyl-phenethyl-{2-{1-(4-piperidin-1-ylmethyl-phenyl)-pyrrolidin-3-yl}-ethyl}-amine;

[0263]1-(2-Nitro-4-pyrrolidin-1-ylmethyl-phenyl)-4-pyrrolidin-1-ylmethyl-piperidine;and

[0264]1-(2-Methyl-4-pyrrolidin-1-ylmethyl-phenyl)-4-pyrrolidin-1-ylmethyl-pyrrolidine.

[0265] Yet even more preferred example compounds include:

[0266]1-{1-(4-Pyrrolidin-1-ylmethyl-phenyl)-piperidin-4-ylmethyl}-piperidin-4-ol;

[0267]1-{1-(4-Pyrrolidin-1-ylmethyl-phenyl)-piperidin-4-ylmethyl}-piperidine;

[0268]4-Pyrrolidin-1-ylmethyl-1-(4-pyrrolidin-1-ylmethyl-phenyl)-piperidine;

[0269]4-{2-{1-(4-Piperidin-1-ylmethyl-phenyl)-pyrrolidin-3-yl}-ethyl}-morpholine;

[0270]Cyclohexyl-{1-(4-pyrrolidin-1-ylmethyl-phenyl)-piperidin-4-ylmethyl}-amine;

[0271]Diethyl-{1-(4-pyrrolidin-1-ylmethyl-phenyl)-piperidin-4-ylmethyl}-amine;

[0272]Diethyl-{2-{1-(4-piperidin-1-ylmethyl-phenyl)-pyrrolidin-3-yl}-ethyl}-amine;and

[0273]1-(2-Methyl-4-pyrrolidin-1-ylmethyl-phenyl)-4-pyrrolidin-1-ylmethyl-pyrrolidine.

[0274] The invention also provides compounds that are useful assynthetic intermediates of the compounds of the invention. Suchcompounds, which themselves may or may not have pharmaceutical activity,include those provided in the schemes and synthetic examples.

[0275] The invention also contemplates compounds isotopically labelledto be detectable by positron emission tomography (PET) or single-photonemission computed tomography (SPECT) useful for studying H₃-mediateddisorders.

[0276] During any of the processes for preparation of the compounds ofthe present invention, it may be necessary and/or desirable to protectsensitive or reactive groups on any of the molecules concerned. Inaddition, compounds of the invention may be modified by using protectinggroups; such compounds, precursors, or prodrugs are also within thescope of the invention. This may be achieved by means of conventionalprotecting groups, such as those described in “Protective Groups inOrganic Chemistry”, ed. J. F. W. McOmie, Plenum Press, 1973; and T. W.Greene & P. G. M. Wuts, “Protective Groups in Organic Synthesis”, 3^(rd)ed., John Wiley & Sons, 1999. The protecting groups may be removed at aconvenient subsequent stage using methods known from the art.

[0277] Hydroxyl Protecting Groups

[0278] Protection for the hydroxyl group includes methyl ethers,substituted methyl ethers, substituted ethyl ethers, substitute benzylethers, and silyl ethers.

[0279] Substituted Methyl Ethers

[0280] Examples of substituted methyl ethers include methyoxymethyl,methylthiomethyl, t-butylthiomethyl, (phenyldimethylsilyl)methoxymethyl,benzyloxymethyl, p-methoxybenzyloxymethyl, (4-methoxyphenoxy)methyl,guaiacolmethyl, t-butoxymethyl, 4-pentenyloxymethyl, siloxymethyl,2-methoxyethoxymethyl, 2,2,2-trichloroethoxymethyl,bis(2-chloroethoxy)methyl, 2-(trimethylsilyl)ethoxymethyl,tetrahydropyranyl, 3-bromotetrahydropyranyl, tetrahydrothiopyranyl,1-methoxycyclohexyl, 4-methoxytetrahydropyranyl,4-methoxytetrahydrothiopyranyl, 4-methoxytetrahydrothiopyranylS,S-dioxido, 1-{(2-chloro-4-methyl)phenyl}-4-methoxypiperidin-4-yl,1,4-dioxan-2-yl, tetrahydrofuranyl, tetrahydrothiofuranyl and2,3,3a,4,5,6,7,7a-octahydro-7,8,8-trimethyl-4,7-methanobenzofuran-2-yl.

[0281] Substituted Ethyl Ethers

[0282] Examples of substituted ethyl ethers include 1-ethoxyethyl,1-(2-chloroethoxy)ethyl, 1-methyl-1-methoxyethyl,1-methyl-1-benzyloxyethyl, 1-methyl-1-benzyloxy-2-fluoroethyl,2,2,2-trichloroethyl, 2-trimethylsilylethyl, 2-(phenylselenyl)ethyl,t-butyl, allyl, p-chlorophenyl, p-methoxyphenyl, 2,4-dinitrophenyl, andbenzyl.

[0283] Substituted Benzyl Ethers

[0284] Examples of substituted benzyl ethers include p-methoxybenzyl,3,4-dimethoxybenzyl, o-nitrobenzyl, p-nitrobenzyl, p-halobenzyl,2,6-dichlorobenzyl, p-cyanobenzyl, p-phenylbenzyl, 2- and 4-picolyl,3-methyl-2-picolyl N-oxido, diphenylmethyl, p, p′-dinitrobenzhydryl,5-dibenzosuberyl, triphenylmethyl, α-naphthyldiphenylmethyl,p-methoxyphenyldiphenylmethyl, di(p-methoxyphenyl)phenylmethyl,tri(p-methoxyphenyl)methyl, 4-(4′-bromophenacyloxy)phenyldiphenylmethyl,4,4′,4″-tris(4,5-dichlorophthalimidophenyl)methyl,4,4′,4″-tris(levulinoyloxyphenyl)methyl,4,4′,4″-tris(benzoyloxyphenyl)methyl,3-(Imidazol-1-ylmethyl)bis(4′,4″-dimethoxyphenyl)methyl,1,1-bis(4-methoxyphenyl)-1′-pyrenylmethyl, 9-anthryl,9-(9-phenyl)xanthenyl, 9-(9-phenyl-10-oxo)anthryl,1,3-benzodithiolan-2-yl, and benzisothiazolyl S,S-dioxido.

[0285] Silyl Ethers

[0286] Examples of silyl ethers include trimethylsilyl, triethylsilyl,triisopropylsilyl, dimethylisopropylsilyl, diethylisopropylsilyl,dimethylthexylsilyl, t-butyidimethylsilyl, t-butyldiphenylsilyl,tribenzylsilyl, tri-p-xylylsilyl, triphenylsilyl, diphenylmethylsilyl,and t-butylmethoxyphenylsilyl.

[0287] Esters

[0288] In addition to ethers, a hydroxyl group may be protected as anester. Examples of esters include formate, benzoylformate, acetate,chloroacetate, dichloroacetate, trichloroacetate, trifluoroacetate,methoxyacetate, triphenylmethoxyacetate, phenoxyacetate,p-chlorophenoxyacetate, p-P-phenylacetate, 3-phenylpropionate,4-oxopentanoate(levulinate), 4,4-(ethylenedithio)pentanoate, pivaloate,adamantoate, crotonate, 4-methoxycrotonate, benzoate, p-phenylbenzoate,2,4,6-trimethylbenzoate(mesitoate)

[0289] Carbonates

[0290] Examples of carbonates include methyl, 9-fluorenylmethyl, ethyl,2,2,2-trichloroethyl, 2-(trimethylsilyl)ethyl, 2-(phenylsulfonyl)ethyl,2-(triphenylphosphonio)ethyl, isobutyl, vinyl, allyl, p-nitrophenyl,benzyl, p-methoxybenzyl, 3,4-dimethoxybenzyl, o-nitrobenzyl,p-nitrobenzyl, S-benzyl thiocarbonate, 4-ethoxy-1-naphthyl, and methyldithiocarbonate.

[0291] Assisted Cleavage

[0292] Examples of assisted cleavage include 2-iodobenzoate,4-azidobutyrate, 4-nitro-4-methylpentanoate, o-(dibromomethyl)benzoate,2-formylbenzenesulfonate, 2-(methylthiomethoxy)ethyl carbonate,4-(methylthiomethoxy)butyrate, and 2-(methylthiomethoxymethyl)benzoate.

[0293] Miscellaneous Esters

[0294] Examples of miscellaneous esters include2,6-dichloro-4-methylphenoxyacetate,2,6-dichloro-4-(1,1,3,3-tetramethylbutyl)phenoxyacetate,2,4-bis(1,1-dimethylpropyl)phenoxyacetate, chlorodiphenylacetate,isobutyrate, monosuccinoate, (E)-2-methyl-2-butenoate(tigloate),o-(methoxycarbonyl)benzoate, p-P-benzoate, α-naphthoate, nitrate, alkylN,N,N′,N′-tetramethylphosphorodiamidate, N-phenylcarbamate, borate,dimethylphosphinothioyl, and 2,4-dinitrophenylsulfenate

[0295] Sulfonates

[0296] Examples of sulfonates include sulfate,methanesulfonate(mesylate), benzylsulfonate, and tosylate.

[0297] Protection for 1,2- and 1,3-Diols

[0298] Cyclic Acetals and Ketals

[0299] Examples of cyclic acetals and ketals include methylene,ethylidene, 1-t-butylethylidene, 1-phenylethylidene,(4-methoxyphenyl)ethylidene, 2,2,2-trichloroethylidene, acetonide(isopropylidene), cyclopentylidene, cyclohexylidene, cycloheptylidene,benzylidene, p-methoxybenzylidene, 2,4-dimethoxybenzylidene,3,4-dimethoxybenzylidene, and 2-nitrobenzylidene.

[0300] Cyclic Ortho Esters

[0301] Examples of cyclic ortho esters include methoxymethylene,ethoxymethylene, dimethoxymethylene, 1-methoxyethylidene,1-ethoxyethylidine, 1,2-dimethoxyethylidene, α-methoxybenzylidene,1-(N,N-dimethylamino)ethylidene derivative,α-(N,N-dimethylamino)benzylidene derivative, and 2-oxacyclopentylidene.

[0302] Silyl Derivatives

[0303] Examples of silyl derivatives include di-t-butylsilylene group,and 1,3-(1,1,3,3-tetraisopropyldisiloxanylidene) derivative.

[0304] Amino Protecting Groups

[0305] Protection for the amino group includes carbamates, amides, andspecial —NH protective groups.

[0306] Examples of carbamates include methyl and ethyl carbamates,substituted ethyl carbamates, assisted cleavage carbamates, photolyticcleavage carbamates, urea-type derivatives, and miscellaneouscarbamates.

[0307] Carbamates

[0308] Examples of methyl and ethyl carbamates include methyl and ethyl,9-fluorenylmethyl, 9-(2-sulfo)fluorenylmethyl,9-(2,7-dibromo)fluorenylmethyl,2,7-di-t-butyl-{9-(10,10-dioxo-10,10,10,10-tetrahydrothioxanthyl)}methyl,and 4-methoxyphenacyl.

[0309] Substituted Ethyl

[0310] Examples of substituted ethyl carbamates include2,2,2-trichloroethyl, 2-trimethylsilylethyl, 2-phenylethyl,1-(1-adamantyl)-1-methylethyl, 1,1-dimethyl-2-haloethyl,1,1-dimethyl-2,2-dibromoethyl, 1,1-dimethyl-2,2,2-trichloroethyl,1-methyl-1-(4-biphenylyl)ethyl, 1-(3,5-di-t-butylphenyl)-1-methylethyl,2-(2′- and 4′-pyridyl)ethyl, 2-(N,N-dicyclohexylcarboxamido)ethyl,t-butyl, 1-adamantyl, vinyl, allyl, 1-isopropylallyl, cinnamyl,4-nitrocinnamyl, 8-quinolyl, N-hydroxypiperidinyl, alkyldithio, benzyl,p-methoxybenzyl, p-nitrobenzyl, p-bromobenzyl, p-chlorobenzyl,2,4-dichlorobenzyl, 4-methylsulfinylbenzyl, 9-anthrylmethyl anddiphenylmethyl.

[0311] Assisted Cleavage

[0312] Examples of assisted cleavage include 2-methylthioethyl,2-methylsulfonylethyl, 2-(p-toluenesulfonyl)ethyl,{2-(1,3-dithianyl)}methyl, 4-methylthiophenyl, 2,4-dimethylthiophenyl,2-phosphonioethyl, 2-triphenylphosphonioisopropyl,1,1-dimethyl-2-cyanoethyl, m-chloro-p-acyloxybenzyl,p-(dihydroxyboryl)benzyl, 5-benzisoxazolylmethyl, and2-(trifluoromethyl)-6-chromonylmethyl.

[0313] Photolytic Cleavage

[0314] Examples of photolytic cleavage include m-nitrophenyl,3,5-dimethoxybenzyl, o-nitrobenzyl, 3,4-dimethoxy-6-nitrobenzyl, andphenyl(o-nitrophenyl)methyl.

[0315] Urea-Type Derivatives

[0316] Examples of urea-type derivatives includephenothiazinyl-(10)-carbonyl derivative,N′-p-toluenesulfonylaminocarbonyl, and N′-phenylaminothiocarbonyl.

[0317] Miscellaneous Carbamates

[0318] Examples of miscellaneous carbamates include t-amyl, S-benzylthiocarbamate, p-cyanobenzyl, cyclobutyl, cyclohexyl, cyclopentyl,cyclopropylmethyl, p-decyloxybenzyl, diisopropylmethyl,2,2-dimethoxycarbonylvinyl, o-(N,N-dimethylcarboxamido)benzyl,1,1-dimethyl-3-(N,N-dimethylcarboxamido)propyl, 1,1-dimethylpropynyl,di(2-pyridyl)methyl, 2-furanylmethyl, 2-iodoethyl, isobornyl, isobutyl,isonicotinyl, p-(p′-methoxyphenylazo)benzyl, 1-methylcyclobutyl,1-methylcyclohexyl, 1-methyl-1-cyclopropylmethyl,1-methyl-1-(3,5-dimethoxyphenyl)ethyl,1-methyl-1-(p-phenylazophenyl)ethyl, 1-methyl-1-phenylethyl,1-methyl-1-(4-pyridyl)ethyl, phenyl, p-(phenylazo)benzyl,2,4,6-tri-t-butylphenyl, 4-(trimethylammonium)benzyl, and2,4,6-trimethylbenzyl.

[0319] Examples of amides include:

[0320] Amides

[0321] N-formyl, N-acetyl, N-chloroacetyl, N-trichloroacetyl,N-trifluoroacetyl, N-phenylacetyl, N-3-phenylpropionyl, N-picolinoyl,N-3-pyridylcarboxamide, N-benzoylphenylalanyl derivative, N-benzoyl,N-p-phenylbenzoyl.

[0322] Assisted Cleavage

[0323] N-o-nitrophenylacetyl, N-o-nitrophenoxyacetyl, N-acetoacetyl,(N′-dithiobenzyloxycarbonylamino)acetyl, N-3-(p-hydroxyphenyl)propionyl,N-3-(o-nitrophenyl)propionyl, N-2-methyl-2-(o-nitrophenoxy)propionyl,N-2-methyl-2-(o-phenylazophenoxy)propionyl, N-4-chlorobutyryl,N-3-methyl-3-nitrobutyryl, N-o-nitrocinnamoyl, N-acetylmethioninederivative, N-o-nitrobenzoyl, N-o-(benzoyloxymethyl)benzoyl, and4,5-diphenyl-3-oxazolin-2-one.

[0324] Cyclic Imide Derivatives

[0325] N-phthalimide, N-dithiasuccinoyl, N-2,3-diphenylmaleoyl,N-2,5-dimethylpyrrolyl, N-1,1,4,4-tetramethyldisilylazacyclopentaneadduct, 5-substituted 1,3-dimethyl-1,3,5-triazacyclohexan-2-one,5-substituted 1,3-dibenzyl-1,3,5-triazacyclohexan-2-one, and1-substituted 3,5-dinitro-4-pyridonyl.

[0326] Special—NH Protective Groups

[0327] Examples of special NH protective groups include:

[0328] N-Alkyl and N-Aryl Amines

[0329] N-methyl, N-allyl, N-{2-(trimethylsilyl)ethoxy}methyl,N-3-acetoxypropyl, N-(1-isopropyl-4-nitro-2-oxo-3-pyrrolin-3-yl),quaternary ammonium salts, N-benzyl, N-4-methoxybenzyl,N-di(4-methoxyphenyl)methyl, N-5-dibenzosuberyl, N-triphenylmethyl,N-(4-methoxyphenyl)diphenylmethyl, N-9-phenylfluorenyl,N-2,7-dichloro-9-fluorenylmethylene, N-ferrocenylmethyl, andN-2-picolylamine N′-oxide.

[0330] Imine Derivatives

[0331] N-1,1-dimethylthiomethylene, N-benzylidene,N-p-methoxybenzylidene, N-diphenylmethylene,N-{(2-pyridyl)mesityl}methylene, and N-(N′,N′-dimethylaminomethylene).

[0332] Protection for the Carbonyl Group

[0333] Acyclic Acetals and Ketals

[0334] Examples of acyclic acetals and ketals include dimethyl,bis(2,2,2-trichloroethyl), dibenzyl, bis(2-nitrobenzyl) and diacetyl.

[0335] Cyclic Acetals and Ketals

[0336] Examples of cyclic acetals and ketals include 1,3-dioxanes,5-methylene-1,3-dioxane, 5,5-dibromo-1,3-dioxane,5-(2-pyridyl)-1,3-dioxane, 1,3-dioxolanes, 4-bromomethyl-1,3-dioxolane,4-(3-butenyl)-1,3-dioxolane, 4-phenyl-1,3-dioxolane,4-(2-nitrophenyl)-1,3-dioxolane, 4,5-dimethoxymethyl-1,3-dioxolane,0,0′-phenylenedioxy and 1,5-dihydro-3H-2,4-benzodioxepin.

[0337] Acyclic Dithio Acetals and Ketals

[0338] Examples of acyclic dithio acetals and ketals includeS,S′-dimethyl, S,S′-diethyl, S,S′-dipropyl, S,S′-dibutyl, S,S′-dipentyl,S,S′-diphenyl, S,S′-dibenzyl and S,S′-diacetyl.

[0339] Cyclic Dithio Acetals and Ketals

[0340] Examples of cyclic dithio acetals and ketals include1,3-dithiane, 1,3-dithiolane and 1,5-dihydro-3H-2,4-benzodithiepin.

[0341] Acyclic Monothio Acetals and Ketals

[0342] Examples of acyclic monothio acetals and ketals includeO-trimethylsilyl-S-alkyl, O-methyl-S-alkyl or —S-phenyl andO-methyl-S-2-(methylthio)ethyl.

[0343] Cyclic Monothio Acetals and Ketals

[0344] Examples of cyclic monothio acetals and ketals include1,3-oxathiolanes.

[0345] Miscellaneous Derivatives

[0346] O-Substituted Cyanohydrins

[0347] Examples of O-substituted cyanohydrins include O-acetyl,O-trimethylsilyl, O-1-ethoxyethyl and O-tetrahydropyranyl.

[0348] Substituted Hydrazones

[0349] Examples of substituted hydrazones include N,N-dimethyl and2,4-dinitrophenyl.

[0350] Oxime Derivatives

[0351] Examples of oxime derivatives include O-methyl, O-benzyl andO-phenylthiomethyl.

[0352] Imines

[0353] Substituted Methylene Derivatives, Cyclic Derivatives

[0354] Examples of substituted methylene and cyclic derivatives includeoxazolidines, 1-methyl-2-(1′-hydroxyalkyl)imidazoles,N,N′-dimethylimidazolidines, 2,3-dihydro-1,3-benzothiazoles,diethylamine adducts, and methylaluminumbis(2,6-di-t-butyl-4-methylphenoxide)(MAD)complex.

[0355] Monoprotection of Dicarbonyl Compounds

[0356] Selective Protection Of α- and β-Diketones

[0357] Examples of selective protection of α- and β-diketones includeenamines, enol acetates, enol ethers, methyl, ethyl, 1-butyl,piperidinyl, morpholinyl, 4-methyl-1,3-dioxolanyl, pyrrolidinyl, benzyl,S-butyl, and trimethylsilyl.

[0358] Cyclic Ketals, Monothio and Dithio Ketals Examples of cyclicketals, monothio and dithio ketals include bismethylenedioxy derivativesand tetramethylbismethylenedioxy derivatives.

[0359] Protection for the Carboxyl Group

[0360] Esters

[0361] Substituted Methyl Esters

[0362] Examples of substituted methyl esters include 9-fluorenylmethyl,methoxymethyl, methylthiomethyl, tetrahydropyranyl, tetrahydrofuranyl,methoxyethoxymethyl, 2-(trimethylsilyl)ethoxymethyl, benzyloxymethyl,phenacyl, p-bromophenacyl, α-methylphenacyl, p-methoxyphenacyl,carboxamidomethyl, and N-phthalimidomethyl.

[0363] 2-Substituted Ethyl Esters

[0364] Examples of 2-substituted ethyl esters include2,2,2-trichloroethyl,

[0365] 2-haloethyl, ω-chloroalkyl, 2-(trimethylsilyl)ethyl,2-methylthioethyl, 1,3-dithianyl-2-methyl,2-(p-nitrophenylsulfenyl)ethyl, 2-(p-toluenesulfonyl)ethyl,

[0366] 2-(2′-pyridyl)ethyl, 2-(diphenylphosphino)ethyl,1-methyl-1-phenylethyl, t-butyl, cyclopentyl, cyclohexyl, allyl,3-buten-1-yl, 4-(trimethylsilyl)-2-buten-1-yl, cinnamyl,α-methylcinnamyl, phenyl, p-(methylmercapto)phenyl and benzyl.

[0367] Substituted Benzyl Esters

[0368] Examples of substituted benzyl esters include triphenylmethyl,diphenylmethyl, bis(o-nitrophenyl)methyl, 9-anthrylmethyl,2-(9,10-dioxo)anthrylmethyl, 5-dibenzosuberyl, 1-pyrenylmethyl,2-(trifluoromethyl)-6-chromylmethyl, 2,4,6-trimethylbenzyl,p-bromobenzyl, o-nitrobenzyl, p-nitrobenzyl, p-methoxybenzyl,2,6-dimethoxybenzyl, 4-(methylsulfinyl)benzyl, 4-sulfobenzyl, piperonyl,4-picolyl and p-P-benzyl.

[0369] Silyl Esters

[0370] Examples of silyl esters include trimethylsilyl, triethylsilyl,t-butyldimethylsilyl, i-propyldimethylsilyl, phenyldimethylsilyl anddi-t-butylmethylsilyl.

[0371] Activated Esters

[0372] Examples of activated esters include thiols.

[0373] Miscellaneous Derivatives

[0374] Examples of miscellaneous derivatives include oxazoles,2-alkyl-1,3-oxazolines, 4-alkyl-5-oxo-1,3-oxazolidines,5-alkyl-4-oxo-1,3-dioxolanes, ortho esters, phenyl group andpentaminocobalt(III) complex.

[0375] Stannyl Esters

[0376] Examples of stannyl esters include triethylstannyl andtri-n-butylstannyl.

[0377] Amides and Hydrazides

[0378] Amides

[0379] Examples of amides include N,N-dimethyl, pyrrolidinyl,piperidinyl, 5,6-dihydrophenanthridinyl, o-nitroanilides,N-7-nitroindolyl, N-8-Nitro-1,2,3,4-tetrahydroquinolyl, andp-P-benzenesulfonamides.

[0380] Hydrazides

[0381] Examples of hydrazides include N-phenyl and N,N′-diisopropyl.

[0382] The compounds of the invention can be prepared according to themethods described in the next section.

[0383] C. Synthesis

[0384] The compounds of the invention can be prepared according totraditional synthetic organic methods and matrix or combinatorialchemistry methods, as shown in Schemes 1-7 below and in Examples 1-82. Aperson of ordinary skill will be aware of variations and adaptations ofthe schemes and examples provided to achieve the compounds of theinvention.

[0385] One skilled in the art will recognize that synthesis of thecompounds of the present invention may be effected by purchasingintermediate or protected intermediate compounds described in any of theschemes disclosed herein. Throughout the schemes when the reactingfunctionality is located at R³, one skilled in the art will recognizethat the choice of R³ is illustrative only and that the reactingfunctionality could also be located at R⁴ or R⁵.

[0386] One skilled in the art will further recognize that during any ofthe processes for preparation of the compounds of the present invention,it may be necessary and/or desirable to protect sensitive or reactivegroups on any of the molecules concerned. This may be achieved by meansof conventional protecting groups, such as those described in“Protective Groups in Organic Chemistry”, ed. J. F. W. McOmie, PlenumPress, 1973; and T. W. Greene & P. G. M. Wuts, “Protective Groups inOrganic Synthesis”, John Wiley & Sons, 1991. The protecting groups maybe removed at a convenient subsequent stage using methods known from theart.

[0387] Compounds of formula (VIII) may be prepared according to theprocesses outlined in Scheme 1.

[0388] A compound of formula (VIII) is prepared as outlined in Scheme 1from a compound of formula (IV). A compound of formula (IV) is reactedwith a reagent capable of introducing a nitrogen-protecting group M¹under nitrogen-protection conditions. In a particularly preferredembodiment, a compound of formula (IV) is reacted with di-tert-butyldicarbonate in DCM at room temperature. A compound of formula (VI) isobtained from a compound of formula (V) by reacting a compound offormula (V) with an oxidizing agent in a solvent at room temperatureunder alcohol oxidizing conditions. In a preferred embodiment, acompound of formula (V) is reacted with 4-methylmorpholine N-oxide andtetrapropylammonium perruthenate in the presence of a dehydrating agentsuch as 4A molecular sieves in a solvent such as DCE or DCM. A compoundof formula (VII) is obtained from a compound of formula (VI) by reactinga compound of formula (VI) with a compound of formula (XXX) underreductive amination conditions in the presence of a reductant such assodium triacetoxyborohydride, sodium cyanoborohydride, or phenylsilanein a solvent such as THF, DCE, DCM, methanol, ethanol, or ether at atemperature between 0 and 80° C. One skilled in the art will recognizethat the use of a promotor or catalyst with acidic character such asorganometallic complexes or carboxylic acids may increase the rate ofthe reaction and/or reduce the formation of by-products. In aparticularly preferred embodiment, a compound of formula (VI) is reactedwith a compound of formula (XXX), acetic acid, and sodiumtriacetoxyborohydride in DCE at room temperature. A compound of formula(VIII) is obtained from a compound of formula (VII) by reacting acompound of formula (VII) with a reagent capable of removing theprotecting group M¹ under nitrogen deprotection conditions. In apreferred embodiment a compound of formula (VII), in which theprotecting group M¹ is tert-butyl carbamoyl, is reacted with an acidsuch as anhydrous hydrogen chloride in a solvent such as dioxane at roomtemperature.

[0389] Compounds of formula (XIII) may be prepared according to theprocesses outlined in Scheme 2.

[0390] A compound of formula (XIII) is prepared as outlined in Scheme 2from a compound of formula (IX). A compound of formula (IX) is reactedwith a reagent capable of converting a compound of formula (IX) to acompound of formula (X), in which M² represents a nitrogen-protectinggroup, under nitrogen-protecting conditions. In a preferred embodiment,the protecting group M² is benzyl and is introduced by reacting acompound of formula (IX) with benzaldehyde under reductive aminationconditions as outlined in Scheme 1, step C. A compound of formula (XI)is obtained from a compound of formula (X) by reacting a compound offormula (X) with an acid in a solvent at a temperature from 0 to 100° C.under ketal hydrolysis conditions. In a particularly preferredembodiment, a compound of formula (X) is reacted with hydrochloric acidin water at 100° C. A compound of formula (XII) is obtained from acompound of formula (XI) by reacting a compound of formula (XI) with acompound of formula (XXX) under reductive amination conditions, asdescribed in Scheme 1, step C. A compound of formula (XIII) is obtainedfrom a compound of formula (XII) by reacting a compound of formula (XII)with a reagent capable of removing the protecting group M². In apreferred embodiment, a compound of formula (XII), in which M²represents the benzyl group, is reacted with a reducing agent such ashydrogen gas in the presence of a hydrogenation catalyst such aspalladium on carbon at room temperature.

[0391] Compounds of formula (XVII) or formula (XX) may be prepared asoutlined according to the processes outlined in Scheme 3.

[0392] A compound of formula (XVII) or formula (XX) is prepared asoutlined in Scheme 3 from a compound of formula (XIV). A compound offormula (XVI) is prepared from a compound of formula (XIV) by reacting acompound of formula (XIV) with a compound of formula (XV) undernucleophilic, aromatic substitution conditions. In a preferredembodiment, a compound of formula (XIV) is reacted with a compound offormula (XV) in the presence of a base such as sodium carbonate,potassium carbonate, cesium carbonate, sodium hydride, ortetramethylguanidine in a solvent such as DMF, DMAC, THF, DME, DCM, orether at a temperature between 0 and 150° C. In a particularly preferredembodiment, a compound of formula (XIV) is reacted with a compound offormula (XV) in the presence of cesium carbonate or potassium carbonatein DMF at 100° C. A compound of formula (XVII) is prepared by reacting acompound of formula (XVI) with a compound of formula (XXXI) underreductive amination conditions, as described in Scheme 1, step C. Acompound of formula (XIX) is obtained from a compound of formula (XIV)by reacting a compound of formula (XIV) with a compound of formula(XVIII) under amine N-arylation conditions. In a preferred embodiment, acompound of formula (XIV) is reacted with a compound of formula (XVIII)in the presence of a metal complex such as copper(II) acetate, a basesuch as triethylamine or 2,6-lutidine in the presence of an airatmosphere in a solvent such as toluene or DCM. One skilled in the artwill recognize that the addition of a carboxylic acid such as myristicacid and/or a drying agent such as 4A molecular sieves may improve theyield of the reaction and/or reduce by-product formation. In aparticularly preferred embodiment, the metal complex is copper(III)acetate, the base is triethylamine, the solvent is DCM, and the reactionis performed in the presence of 4A molecular sieves. A compound offormula (XX) is prepared by reacting a compound of formula (XIX) with acompound of formula (XXXI) under reductive amination conditions, asdescribed in Scheme 1, step C.

[0393] Compounds of formula (XXIV) may be prepared according to theprocesses outlined in Scheme 4.

[0394] A compound of formula (XXIV) is prepared as outlined in Scheme 4from a compound of formula (IV). A compound of formula (IV) is reactedwith a compound of formula (XV) under nucleophilic aromatic substitutionconditions, as described in Scheme 3, step A. A compound of formula(XXI) is reacted with a compound of formula (XXXI) under reductiveamination conditions, as described in Scheme 1, step C. A compound offormula (XXIII) is prepared from a compound of formula (XXII) byreacting a compound of formula (XXII) with an oxidizing agent underalcohol oxidizing conditions. In a preferred embodiment, a compound offormula (XXII) is reacted with an oxidant such as DMSO in combinationwith oxalyl chloride in the presence of an organic base such astriethylamine in a solvent such as DCM at a temperature from −78° C. toroom temperature. A compound of formula (XXIV) is obtained by reacting acompound of formula (XXIII) with a compound of formula (XXX) underreductive amination conditions, as described in Scheme 1, step C.

[0395] Compounds of formula (XXVI) may be prepared according to theprocesses outlined in Scheme 5.

[0396] A compound of formula (XXVI) is prepared from a compound offormula (XXI) as shown in Scheme 5. A compound of formula (XXV) isprepared by reacting a compound of formula (XXI) under alcohol oxidationconditions as described in Scheme 4, step C. A compound of formula(XXVI) is prepared by reacting a compound of formula (XXV) with acompound of formula (XXX) under reductive amination conditions asdescribed in Scheme 1, step C.

[0397] Compounds of formula (XXXIII) may be prepared according to theprocesses outlined in Scheme 6.

[0398] A compound of formula (XXXIII) is prepared as outlined in Scheme6 from a compound of formula (IX). A compound of formula (XXVII) isprepared from a compound of formula (IX) by reacting a compound offormula (IX) with a compound of formula (XV) under nucleophilic,aromatic substitution conditions as described in Scheme 3, step A. Acompound of formula (XXVIII) is prepared from a compound of formula(XXVII) by reacting a compound formula (XXVII) with a compound offormula (XXXI) under reductive amination conditions as described inScheme 1, step C. A compound of formula (XXIX) is prepared from acompound of formula (XXVIII) by reacting a compound of formula (XXVIII)under ketal hydrolysis conditions as outlined in Scheme 2, step B. Acompound of formula (XXXIII) is prepared by reacting a compound offormula (XXIX) with a compound of formula (XXX) under reductiveamination conditions as described in Scheme 1, step C.

[0399] Compounds of formula (XXXIV) may be prepared according to theprocesses outlined in Scheme 7.

[0400] A compound of formula (XXXIV) is prepared from a compound offormula (XXII) as shown in Scheme 7. A compound of formula (XXXIV) isprepared by reacting a compound of formula (XXII) with a compound offormula (XXX) under rearranging, nucleophilic substitution conditions.In a preferred embodiment, a compound of formula (XXII) is reacted witha compound of formula (XXX) in the presence of a reagent capable ofconverting the hydroxyl functionality to a leaving group such astrimethylcyanomethylphosphonium iodide and a base such asN-ethyl-N,N-diisopropylamine in a solvent such as acetonitrile orpropionitrile at a temperature from 0° C. to 100° C. In a particularlypreferred embodiment, a compound of formula (XXII) is reacted with acompound of formula (XXX) in the presence oftrimethylcyanomethylphosphonium iodide and N-ethyl-N,N-diisopropylaminein propionitrile at 90° C.

[0401] D. Formulation, Administration, and Therapy

[0402] The disclosed compounds, alone or in combination (with, forexample, a histamine H₁ receptor antagonist), are useful for treating orpreventing neurologic disorders including sleep/wake andarousal/vigilance disorders (e.g. insomnia and jet lag), attentiondeficit hyperactivity disorders (ADHD), learning and memory disorders,cognitive dysfunction, migraine, neurogenic inflammation, dementia, mildcognitive impairment (pre-dementia), Alzheimer's disease, epilepsy,narcolepsy, eating disorders, obesity, motion sickness, vertigo,schizophrenia, substance abuse, bipolar disorders, manic disorders anddepression, as well as other histamine H₃ receptor mediated disorderssuch as upper airway allergic response, asthma, itch, nasal congestionand allergic rhinitis in a subject in need thereof.

[0403] 1. Formulation and Administration

[0404] The compounds or compositions of the invention may be formulatedand administered to a subject by any conventional route ofadministration, including, but not limited to, intravenous, oral,subcutaneous, intramuscular, intradermal and parenteral administration.The quantity of the compound that is effective for treating eachcondition may vary, and can be determined by one of ordinary skill inthe art.

[0405] For use in medicine, the salts of the compounds of this inventionrefer to non-toxic “pharmaceutically acceptable salts.” Other salts may,however, be useful in the preparation of compounds according to thisinvention or of their pharmaceutically acceptable salts. Suitablepharmaceutically acceptable salts of the compounds include acid additionsalts that may, for example, be formed by mixing a solution of thecompound with a solution of a pharmaceutically acceptable acid such ashydrochloric acid, sulfuric acid, fumaric acid, maleic acid, succinicacid, acetic acid, benzoic acid, citric acid, tartaric acid, carbonicacid or phosphoric acid. Furthermore, where the compounds of theinvention carry an acidic moiety, suitable pharmaceutically acceptablesalts thereof may include alkali metal salts, e.g., sodium or potassiumsalts; alkaline earth metal salts, e.g., calcium or magnesium salts; andsalts formed with suitable organic ligands, e.g., quaternary ammoniumsalts.

[0406] Thus, representative pharmaceutically acceptable salts includethe following: acetate, benzenesulfonate, benzoate, bicarbonate,bisulfate, bitartrate, borate, bromide, calcium edetate, camsylate,carbonate, chloride, clavulanate, citrate, dihydrochloride, edetate,edisylate, estolate, esylate, fumarate, gluceptate, gluconate,glutamate, glycollylarsanilate, hexylresorcinate, hydrabamine,hydrobromide, hydrochloride, hydroxynaphthoate, iodide, isothionate,lactate, lactobionate, laurate, malate, maleate, mandelate, mesylate,methylbromide, methylnitrate, methylsulfate, mucate, napsylate, nitrate,N-methylglucamine ammonium salt, oleate, pamoate (embonate), palmitate,pantothenate, phosphate/diphosphate, polygalacturonate, salicylate,stearate, sulfate, subacetate, succinate, tannate, tartrate, teoclate,tosylate, triethiodide and valerate.

[0407] The present invention includes within its scope prodrugs of thecompounds of this invention. In general, such prodrugs will befunctional derivatives of the compounds that are readily convertible invivo into the required compound. Thus, in the methods of treatment ofthe present invention, the term “administering” shall encompass thetreatment of the various disorders described with the compoundspecifically disclosed or with a compound that may not be specificallydisclosed, but which converts to the specified compound in vivo afteradministration to the patient. Conventional procedures for the selectionand preparation of suitable prodrug derivatives are described, forexample, in “Design of Prodrugs”, ed. H. Bundgaard, Elsevier, 1985. Inaddition to salts, the invention provides the esters, amides, and otherprotected or derivatized forms of the described compounds.

[0408] Where the compounds according to this invention have at least onechiral center, they may accordingly exist as enantiomers. Where thecompounds possess two or more chiral centers, they may additionallyexist as diastereomers. It is to be understood that all such isomers andmixtures thereof are encompassed within the scope of the presentinvention. Furthermore, some of the crystalline forms for the compoundsmay exist as polymorphs and as such are intended to be included in thepresent invention. In addition, some of the compounds may form solvateswith water (i.e., hydrates) or common organic solvents, and suchsolvates are also intended to be encompassed within the scope of thisinvention.

[0409] The present invention also provides pharmaceutical compositionscomprising one or more compounds of this invention in association with apharmaceutically acceptable carrier and optionally additionalpharmaceutical agents such as H₁ antagonists or SSRIs. Preferably thesecompositions are in unit dosage forms such as pills, tablets, caplets,capsules (each including immediate release, timed release and sustainedrelease formulations), powders, granules, sterile parenteral solutionsor suspensions (including syrups and emulsions), metered aerosol orliquid sprays, drops, ampoules, autoinjector devices or suppositories;for oral, parenteral, intranasal, sublingual or rectal administration,or for administration by inhalation or insufflation. Alternatively, thecomposition may be presented in a form suitable for once-weekly oronce-monthly administration; for example, an insoluble salt of theactive compound, such as the decanoate salt, may be adapted to provide adepot preparation for intramuscular injection. For preparing solidcompositions such as tablets, the principal active ingredient is mixedwith a pharmaceutical carrier, e.g. conventional tableting ingredientssuch as corn starch, lactose, sucrose, sorbitol, talc, stearic acid,magnesium stearate, dicalcium phosphate or gums, and otherpharmaceutical diluents, e.g. water, to form a solid pre-formulationcomposition containing a homogeneous mixture of a compound of thepresent invention, or a pharmaceutically acceptable salt thereof. Whenreferring to these pre-formulation compositions as homogeneous, it ismeant that the active ingredient is dispersed evenly throughout thecomposition so that the composition may be readily subdivided intoequally effective dosage forms such as tablets, pills and capsules. Thissolid pre-formulation composition is then subdivided into unit dosageforms of the type described above containing from 5 to about 1000 mg ofthe active ingredient of the present invention. Examples include 5 mg, 7mg, 10 mg, 15 mg, 20 mg, 35 mg, 50 mg, 75 mg, 100 mg, 120 mg, 150 mg,and so on. The tablets or pills of the disclosed compositions can becoated or otherwise compounded to provide a dosage form affording theadvantage of prolonged action. For example, the tablet or pill cancomprise an inner dosage and an outer dosage component, the latter beingin the form of an envelope over the former. The two components can beseparated by an enteric layer, which serves to resist disintegration inthe stomach and permits the inner component to pass intact into theduodenum or to be delayed in release. A variety of material can be usedfor such enteric layers or coatings, such materials including a numberof polymeric acids with such materials as shellac, cetyl alcohol andcellulose acetate.

[0410] The liquid forms in which the compounds and compositions of thepresent invention may be incorporated for administration orally or byinjection include, aqueous solutions, suitably flavored syrups, aqueousor oil suspensions, and flavored emulsions with edible oils such ascottonseed oil, sesame oil, coconut oil or peanut oil, as well aselixirs and similar pharmaceutical vehicles. Suitable dispersing orsuspending agents for aqueous suspensions, include synthetic and naturalgums such as tragacanth, acacia, alginate, dextran, sodiumcarboxymethylcellulose, methylcellulose, polyvinyl-pyrrolidone orgelatin.

[0411] Where the processes for the preparation of the compoundsaccording to the invention give rise to mixture of stereoisomers, theseisomers may be separated by conventional techniques such as preparativechromatography. The compounds may be prepared in racemic form, orindividual enantiomers may be prepared either by enantiospecificsynthesis or by resolution. The compounds may, for example, be resolvedinto their component enantiomers by standard techniques, such as theformation of diastereomeric pairs by salt formation with an opticallyactive acid, such as (−)-di-p-toluoyl-d-tartaric acid and/or(+)-di-p-toluoyl-1-tartaric acid followed by fractional crystallizationand regeneration of the free base. The compounds may also be resolved byformation of diastereomeric esters or amides, followed bychromatographic separation and removal of the chiral auxiliary.Alternatively, the compounds may be resolved using a chiral HPLC column.

[0412] Advantageously, compounds of the present invention may beadministered in a single daily dose, or the total daily dosage may beadministered in divided doses of two, three or four times daily.Furthermore, compounds for the present invention can be administered inintranasal form via topical use of suitable intranasal vehicles, or viatransdermal skin patches well known to those of ordinary skill in thatart. To be administered in the form of a transdermal delivery system,the dosage administration will, of course, be continuous rather thanintermittent throughout the dosage regimen.

[0413] For instance, for oral administration in the form of a tablet orcapsule, the active drug component can be combined with an oral,non-toxic pharmaceutically acceptable inert carrier such as ethanol,glycerol, water and the like. Moreover, when desired or necessary,suitable binders, lubricants, disintegrating agents and coloring agentscan also be incorporated into the mixture. Suitable binders include,without limitation, starch, gelatin, natural sugars such as glucose orbeta-lactose, corn sweeteners, natural and synthetic gums such asacacia, tragacanth or sodium oleate, sodium stearate, magnesiumstearate, sodium benzoate, sodium acetate, sodium chloride and the like.Disintegrators include, without limitation, starch, methyl cellulose,agar, bentonite, xanthan gum and the like.

[0414] The compound of the present invention can also be administered inthe form of liposome delivery systems, such as small unilamellarvesicles, large unilamellar vesicles, and multilamellar vesicles.Liposomes can be formed from a variety of phospholipids, such ascholesterol, stearylamine or phophatidylcholines.

[0415] Compounds of the present invention may also be delivered by theuse of monoclonal antibodies as individual carriers to which thecompound molecules are coupled. The compounds of the present inventionmay also be coupled with soluble polymers as targetable drug carriers.Such polymers can include polyvinylpyrrolidone, pyran copolymer,polyhydroxypropylmethacrylamidephenol,polyhydroxyethylaspartamidephenol, or polyethyleneoxidepolylysinesubstituted with palmitoyl residue. Furthermore, the compounds of thepresent invention may be coupled to a class of biodegradable polymersuseful in achieving controlled release of a drug, for example,polylactic acid, polyepsilon caprolactone, polyhydroxy butyric acid,polyoesters, polyacetals, polydihydropyrans, polycyanoacrylates andcross-linked or amphipathic block copolymers of hydrogels.

[0416] Compounds of this invention may be administered in any of theforegoing compositions and according to dosage regimens established inthe art whenever treatment is required.

[0417] The daily dosage of the products may be varied over a wide rangefrom 1 to 1,000 mg per adult human per day. For oral administration, thecompositions are preferably provided in the form of tablets containing1.0, 5.0, 10.0, 15.0, 25.0, 50.0, 100, 250 and 500 milligrams of theactive ingredient for the symptomatic adjustment of the dosage to thesubject to be treated. An effective amount of the drug is ordinarilysupplied at a dosage level of from about 0.01 mg/kg to about 20 mg/kg ofbody weight per day. Preferably, the range is from about 0.02 mg/kg toabout 10 mg/kg of body weight per day, and especially from about 0.05mg/kg to about 10 mg/kg of body weight per day. The compounds may beadministered on a regimen of 1 to 4 times per day.

[0418] Optimal dosages to be administered may be readily determined bythose skilled in the art, and will vary with the particular compoundused, the mode of administration, the strength of the preparation, themode of administration, and the advancement of the disease condition. Inaddition, factors associated with the particular patient being treated,including patient age, weight, diet and time of administration, willresult in the need to adjust dosages.

[0419] 2. Combination Therapy

[0420] The disclosed compounds are useful in combination with othertherapeutic agents, including H₁ receptor antagonists, H₂ receptorantagonists, and neurotransmitter modulators such as SSRIs andnon-selective serotonin re-uptake inhibitors (NSSRIs).

[0421] Methods are known in the art for determining effective doses fortherapeutic and prophylactic purposes for the disclosed pharmaceuticalcompositions or the disclosed drug combinations, whether or notformulated in the same composition. For therapeutic purposes, the term“jointly effective amount” as used herein, means that amount of eachactive compound or pharmaceutical agent, alone or in combination, thatelicits the biological or medicinal response in a tissue system, animalor human that is being sought by a researcher, veterinarian, medicaldoctor or other clinician, which includes alleviation of the symptoms ofthe disease or disorder being treated. For prophylactic purposes (i.e.,inhibiting the onset or progression of a disorder), the term “jointlyeffective amount” refers to that amount of each active compound orpharmaceutical agent, alone or in combination, that inhibits in asubject the onset or progression of a disorder as being sought by aresearcher, veterinarian, medical doctor or other clinician, thedelaying of which disorder is mediated, at least in part, by themodulation of one or more histamine receptors. Thus, the presentinvention provides combinations of two or more drugs wherein, forexample, (a) each drug is administered in an independentlytherapeutically or prophylactically effective amount; (b) at least onedrug in the combination is administered in an amount that issub-therapeutic or sub-prophylactic if administered alone, but istherapeutic or prophylactic when administered in combination with thesecond or additional drugs according to the invention; or (c) both drugsare administered in an amount that is sub-therapeutic orsub-prophylactic if administered alone, but are therapeutic orprophylactic when administered together. Combinations of three or moredrugs are analogously possible. Methods of combination therapy includeco-administration of a single formulation containing all active agents;essentially contemporaneous administration of more than one formulation;and administration of two or more active agents separately formulated.

E. EXAMPLES

[0422] In order to illustrate the invention, the following examples areincluded. These examples do not limit the invention. They are only meantto suggest a method of practicing the invention. Those skilled in theart may find other methods of practicing the invention, which areobvious to them. However, those methods are deemed to be within thescope of this invention.

Protocol for Preparative Reversed-Phase HPLC

[0423] Gilson®

[0424] Column: YMC-Pack ODS-A, 5 μm, 75×30 mm

[0425] Flow rate: 25 mL/min

[0426] Detection: λ=220 & 254 nm

[0427] Gradient (acetonitrile/water, 0.05% trifluoroacetic acid)

[0428] 1) 0.0 min 15% acetonitrile/85% water

[0429] 2) 20.0 min 99% acetonitrile/1% water

Protocol for HPLC (Reversed-Phase)

[0430] Hewlett Packard Series 1100

[0431] Column: Agilent ZORBAX® Bonus RP, 5 μm, 4.6×250 mm

[0432] Flow rate: 1 mL/min

[0433] Detection: λ=220 & 254 nm

[0434] Gradient (acetonitrile/water, 0.05% trifluoroacetic acid)

[0435] 1) 0.0 min 1% acetonitrile/99% water

[0436] 2) 20.0 min 99% acetonitrile/1% water

[0437] Mass spectra were obtained on an Agilent series 1100 MSD usingelectrospray ionization (ESI) in either positive or negative modes asindicated.

[0438] Thin-layer chromatography was performed using Merck silica gel 60F₂₅₄ 2.5 cm×7.5 cm 250 μm or 5.0 cm×10.0 cm 250 μm pre-coated silica gelplates. Preparative thin-layer chromatography was performed using EMScience silica gel 60 F₂₅₄ 20 cm×20 cm 0.5 mm pre-coated plates with a20 cm×4 cm concentrating zone.

[0439] NMR spectra were obtained on either a Bruker model DPX400 (400MHz) or DPX500 (500 MHz) spectrometer. The format of the ¹H NMR databelow is: chemical shift in ppm down field of the tetramethylsilanereference (multiplicity, coupling constant J in Hz, integration).

Example 1

[0440]

[0441] 4-Hydroxymethyl-piperidine-1-carboxylic Acid Tert-Butyl Ester

[0442] To a solution of 4-piperidinemethanol (37.2 g) in dichloromethane(DCM, 300 mL) was added di-tert-butyl dicarbonate (70.5 g) in severalportions. The resulting mixture was stirred at room temperatureovernight. The reaction mixture was diluted with DCM (700 mL), andwashed with water (200 mL), saturated ammonium chloride (200 mL) andbrine (200 mL). The combined extracts were dried (MgSO₄) andconcentrated under reduced pressure, giving the title compound as awhite solid (69.5 g).

Example 2

[0443]

[0444] 4-Formyl-piperidine-1-carboxylic Acid Tert-Butyl Ester

[0445] To a mixture of the product of Example 1 (23.1 g),4-methylmorpholine N-oxide (NMO, 18.9 g) and 4A molecular sieves (53.5g) in DCM (214 mL) was added tetrapropylammonium perruthenate (TPAP, 1.9g) portion-wise at room temperature. The reaction mixture was stirred atroom temperature for 1 h and filtered through a pad of silica gel.Evaporation of solvent gave the title compound as a light yellow oil(15.0 g).

Example 3

[0446]

[0447] 4-Pyrrolidin-1-vimethyl-piperidine-1-carboxylic Acid Tert-ButylEster

[0448] To a solution of the product of Example 2 (2.0 g) in DCM (40 mL)was added pyrrolidine (1.0 g) followed by sodium triacetoxyborohydride(2.8 g). The resulting mixture was stirred overnight, and treated with10% NaOH (20 mL). The resulting mixture was extracted with DCM (300 mL).The combined extracts were washed with water (50 mL) and brine (50 mL),dried (MgSO₄), and concentrated under reduced pressure to give the titlecompound as a light pink-brown oil (2.4 g).

Example 4

[0449]

[0450] 4-Pyrrolidin-1-ylmethyl-Piperidine

[0451] To a solution of the product of Example 3 (2.4 g) in dioxane (30mL) was added 4 N HCl in dioxane (30 mL). The resulting mixture wasstirred at room temperature overnight, concentrated, and treated with10% NaOH (50 mL). The resulting mixture was extracted with DCM (2×100mL). The combined extracts were washed with water (30 mL) and brine (30mL), and concentrated under reduced pressure to give the title compoundas a brown-yellow oil (0.81 g).

Example 5

[0452]

[0453] 4-{1,4′}Bipiperidinyl-1′-yl-benzaldehyde

[0454] A mixture of 4-fluorobenzaldehyde (1 mL), {1,4′}bipiperidinyl(829.6 mg), and potassium carbonate (0.72 g) in DMF (3 mL) was heated to100° C. for 6 h. The cooled reaction mixture was poured into water (200mL) and then extracted with DCM. Removal of the solvent andchromatography of the residue on silica gel (1-7% 2 M methanolicammonia/DCM) gave the title compound (838.3 mg).

Example 6

[0455]

[0456] 4-(4-Hydroxymethyl-piperidin-1-yl)-benzaldehyde

[0457] A suspension of 4-fluorobenzaldehyde (4.3 mL),4-hydroxymethylpiperidine (4.8 g), and cesium carbonate (26 g) in DMF(80 mL) was heated to 100° C. for 24 h and cooled to room temperature.Water (400 mL) was added, and the resulting precipitate was collected byfiltration to give the title compound as a tan amorphous powder (4.1 g).

[0458] The compounds of Example 7 through Example 9 were preparedaccording to the procedure of Example 6 from the specifiedfluorobenzaldehde and secondary amine.

Example 7

[0459]

[0460] 2-(4-Hydroxymethyl-piperidin-1-yl)-benzaldehyde

[0461] Prepared from 2-fluorobenzaldehyde and 4-hydroxymethylpiperidine.

Example 8

[0462]

[0463] 4-(1,4-Dioxa-8-aza-spiro{4,5}dec-8-yl)-benzaldehyde

[0464] Prepared from 4-fluorobenzaldehyde and1,4-dioxa-8-aza-spiro{4.5}decane.

Example 9

[0465]

[0466] 4-(4-Pyrrolidin-1-ylmethyl-pieridin-1-yl)-benzaldehyde

[0467] Prepared from 4-fluorobenzaldehyde and the product of Example 4.

Example 10

[0468]

[0469] {1-(4-Piperidin-1-ylmethyl-phenyl)-piperidin-4-yl}-methanol

[0470] A solution of the product of Example 6 (1.3 g) and piperidine(0.70 mL) in DCM (11 mL) was treated with sodium triacetoxyborohydride(1.9 g). After 16 h, the resulting mixture was treated with 10% aqueouspotassium hydroxide (10 mL). The aqueous phase was extracted with DCM(3×10 mL), and the combined organic phases were dried (MgSO₄), andconcentrated under reduced pressure, giving the title compound as awhite waxy solid (1.5 g).

[0471] The compounds of Example 11 through Example 14 were preparedaccording to the procedure of Example 10, using the specified aldehydesand amines.

Example 11

[0472]

[0473] {1-(4-Pyrrolidin-1-ylmethyl-phenyl)-piperidin-4-yl}-methanol

[0474] Prepared from the product of Example 6 and pyrrolidine.

Example 12

[0475]

[0476] {1-(2-Morpholin-4-ylmethyl-phenyl)-piperidin-4-yl}-methanol

[0477] Prepared from the product of Example 7 and morpholine.

Example 13

[0478]

[0479] {1-(4-Morpholin-4-ylmethyl-phenyl)-piperidin-4-yl}-methanol

[0480] Prepared from the product of Example 6 and morpholine.

Example 14

[0481]

[0482]8-(4-Morpholin-4-ylmethyl-phenyl)-1,4-dioxa-8-aza-spiro{4,5}decane

[0483] Prepared from the product of Example 8 and morpholine.

Example 15

[0484]

[0485] 1-(4-Piperidin-1-ylmethyl-phenyl)-piperidine-4-carbaldehyde Asolution of oxalyl chloride (1.0 mL) in DCM (4 mL) was cooled in a −78°C. bath and treated with DMSO (0.17 mL). After 5 min, a solution of theproduct of Example 10 in DCM (2 mL) was added dropwise. After 30 min,triethylamine (0.59 mL) was added, and the reaction mixture was allowedto warm to room temperature. Water (2 mL) was added, and the resultingmixture was extracted with DCM (3×3 mL). The combined extracts weredried (MgSO₄) and concentrated under reduced pressure, giving the titlecompound, which was used without further purification.

[0486] The compounds of Example 16 through Example 18 were preparedaccording to the procedure of Example 15 using the specified alcohol.

Example 16

[0487]

[0488] 1-(4-Pyrrolidin-1-ylmethyl-phenyl)-piperidine-4-carbaldehyde

[0489] Prepared from the product of Example 11.

Example 17

[0490]

[0491] 1-(2-Morpholin-4-ylmethyl-phenyl)-piperidine-4-carbaldehyde

[0492] Prepared from the product of Example 12.

Example 18

[0493]

[0494] 1-(4-Morpholin-4-ylmethyl-phenyl)-piperidine-4-carbaldehyde

[0495] Prepared from the product of Example 13.

Example 19

[0496]

[0497] 1-(4-Morpholin-4-ylmethyl-phenyl)-piperidin-4-one

[0498] The product of Example 14 (4.5 g) was treated with 6 M HCl (50mL), heated to 100° C. for 90 min, and then cooled to room temperature.The resulting solution was basified with 10% aqueous NaOH to pH 11, andextracted with DCM (3×5 mL). The combined extracts were dried (MgSO₄),and concentrated under reduced pressure, giving the title compound as abrown gummy solid (4.3 g).

Example 20

[0499]

[0500] 3-(4-Pyrrolidin-1-ylmethyl-piperidin-1-yl)-benzaldehyde

[0501] To a mixture of 3-formylphenylboronic acid (2.5 g) and piperidine(1.4 g) in DCM (200 mL) was added 4A molecular sieves (5 g) andcopper(II) acetate (1.5 g) sequentially. The reaction mixture wasstirred at room temperature for four days, filtered through a pad ofCelite®, and concentrated under reduced pressure. Purification of theresidue by silica gel chromatography (0-10% 2 M methanolic ammonia/DCM)afforded the title compound as a yellow solid (0.79 g).

Example 21

[0502]

[0503] 1-(4-Formyl-phenyl)-piperidine-4-carbaldehyde

[0504] Oxalyl chloride (2.5 mL, 2.0 M) was added to a cooled (−78° C.)solution of DMSO (0.7 mL) in DCM (3 mL). After 20 min a solution of theproduct from Example 6 (0.38 g) in DCM (3 mL) was added. This mixturewas aged for an additional 20 min. Triethylamine was then added and thecold bath (CO₂/acetone) was removed. The mixture was allowed to reachambient temperature. After 1 h the mixture was poured into water (100mL) and extracted with DCM. Removal of the solvent gave the titlecompound (0.38 g), which was used without further purification.

Example 22

[0505]

[0506] 4-{2-(4-piperidin-1-ylmethyl-piperidin-1-yl)-benzyl}-morpholine

[0507] A solution of the product of Example 17 (288 mg) and piperidine(0.12 mL) in dichloroethane (DCE, 2 mL) was treated with sodiumtriacetoxyborohydride (297 mg). After 16 h, the resulting mixture wastreated with 10% potassium hydroxide (2 mL), and extracted with DCM (2×2mL). The combined extracts were dried (MgSO₄), and chromatographed onsilica gel (0-8% 2 M methanolic ammonia/DCM), giving the title compoundas a colorless oil (100 mg).

[0508]¹H NMR (400 MHz, CDCl₃): 7.42 (dd, J=7.6, 1.6 Hz, 1H), 7.21 (t,J=8.0, 1.8 Hz, 1H), 7.02 (ddd, J=8.0, 8.0, 1.0 Hz, 1H), 7.02 (ddd,J=7.4, 7.4, 1.2 Hz, 1H), 3.68 (t, J=4.7 Hz, 4H), 3.54 (s, 2H), 3.21-3.15(m, 2H), 2.63 (ddd, J=11.7, 11.7, 2.2 Hz, 2H), 2.50-2.45 (br m, 4H),2.41-2.37 (br m, 4H), 2.22 (d, J=7.0 Hz, 2H), 1.85-1.79 (m, 2H),1.70-1.56 (m, 5H), 1.47-1.30 (m, 4H).

[0509] The compounds in Example 23 through Example 52 were preparedaccording to the procedure of Example 22 using the specified carbonylcompound and amine.

Example 23

[0510]

[0511]Cyclohexyl-{1-(4-pyrrolidin-1-ylmethyl-phenyl)-piperidin-4-ylmethyl}-amine

[0512] Prepared from the product of Example 16 and cyclohexylamine.

[0513]¹H NMR (400 MHz, CDCl₃): 7.19 (d, J=8.6 Hz, 2H), 6.90-6.87 (m,2H), 3.66 (d, J=12.2 Hz, 2H), 3.52 (s, 2H), 2.71-2.64 (m, 2H), 2.55 (d,J=6.7 Hz, 4H), 2.49-2.43 (m, 4H), 2.42-2.36 (m, 1H), 1.90-1.53 (m, 11H),1.41-1.01 (m, 8H).

Example 24

[0514]

[0515]1-{1-(4-Pyrrolidin-1-ylmethyl-phenyl)-piperidin-4-ylmethyl}-azacyclotridecane

[0516] Prepared from the product of Example 16 and dodecamethyleneamine.

[0517]¹H NMR (400 MHz, CDCl₃): 7.19 (d, J=8.6 Hz, 2H), 6.89 (d, J=8.6Hz, 2H), 3.65 (d, J=12.3 Hz, 2H), 3.53 (s, 2H), 2.71-2.63 (m, 2H), 2.49(br s, 4H), 2.32-2.31 (m, 4H), 2.15 (d, J=6.9 Hz, 2H), 1.90 (d, J=13.0Hz, 2H), 1.79-1.73 (m, 4H), 1.63-1.24 (m, 23H).

Example 25

[0518]

[0519]Diethyl-{1-(4-pyrrolidin-1-ylmethyl-phenyl)-piperidin-4-ylmethyl}-amine

[0520] Prepared from the product of Example 16 and diethylamine.

[0521]¹H NMR (400 MHz, CDCl₃): 7.19 (d, J=8.5 Hz, 2H), 6.89 (d, J=8.6Hz, 2H), 3.65 (d, J=12.3 Hz, 2H), 3.52 (s, 2H), 2.70-2.64 (m, 2H),2.53-2.48 (m, 8H), 2.25 (d, J=7.0 Hz, 2H), 1.86 (d, J=12.5 Hz, 2H),1.78-1.73 (m, 4H), 1.58-1.51 (m, 1H), 1.36-1.26 (m, 2H), 1.01 (t, J=7.1Hz, 6H).

Example 26

[0522]

[0523]Dimethyl-{1-(4-pyrrolidin-1-ylmethyl-phenyl)-piperidin-4-ylmethyl}-amine

[0524] Prepared from the product of Example 16 and dimethylaminehydrochloride.

[0525]¹H NMR (400 MHz, CDCl₃): 7.19 (d, J=8.5 Hz, 2H), 6.89 (d, J=8.6Hz, 2H), 3.66 (d, J=12.3 Hz, 2H), 3.53 (s, 2H), 2.71-2.64 (m, 2H), 2.48(br s, 4H), 2.22 (s, 6H), 2.15 (d, J=7.2 Hz, 2H), 1.85 (d, J=13.0 Hz,2H), 1.80-1.73 (m, 4H), 1.64-1.55 (m, 1H), 1.38-1.26 (m, 2H).

Example 27

[0526]

[0527]1-Methyl-4-{1-(4-pyrrolidin-1-vimethyl-phenyl)-piperidin-4-ylmethyl}-piperazine

[0528] Prepared from the product of Example 16 and N-methylpiperazine.

[0529]¹H NMR (400 MHz, CDCl₃): 7.19 (d, J=8.5 Hz, 2H), 6.89 (d, J=8.5Hz, 2H), 3.54 (s, 2H), 2.69-2.35 (m, 12H), 2.29 (s, 3H), 2.22 (d, J=7.2Hz, 2H), 1.87-1.59 (m, 9H), 1.38-1.26 (m, 2H).

Example 28

[0530]

[0531]1-{1-(4-Pyrrolidin-1-ylmethyl-phenyl)-piperidin-4-ylmethyl}-piperidin-4-ol

[0532] Prepared from the product of Example 16 and 4-hydroxypiperidine.

[0533]¹H NMR (400 MHz, CDCl₃): 7.20 (d, J=8.5 Hz, 2H), 6.89 (d, J=8.5Hz, 2H), 3.71-3.64 (m, 3H), 3.54 (s, 2H), 2.75-2.63 (m, 4H), 2.50 (br s,4H), 2.19 (d, J=7.8 Hz, 2H), 2.09 (t, J=10.1 Hz, 2H), 1.91-1.54 (m,12H), 1.38-1.24 (m, 3H).

Example 29

[0534]

[0535]4-{1-(4-Pyrrolidin-1-ylmethyl-phenyl)-piperidin-4-ylmethyl}-thiomorpholine

[0536] Prepared from the product of Example 16 and thiomorpholine.

[0537]¹H NMR (400 MHz, CDCl₃): 7.20 (d, J=8.8 Hz, 2H), 6.89 (d, J=8.6Hz, 2H), 3.65 (d, J=12.3 Hz, 2H), 3.53 (s, 2H), 3.14-3.10 (m, 1H),2.71-2.58 (m, 10H), 2.52-2.46 (m, 4H), 2.22 (d, J=7.0 Hz, 2H), 1.87-1.74(m, 6H), 1.68-1.56 (m, 2H), 1.31 (ddd, J=12.2 Hz, 12.2 Hz, 3.9 Hz, 2H).

Example 30

[0538]

[0539]1-{1-(4-Pyrrolidin-1-ylmethyl-phenyl)-piperidin-4-ylmethyl}-piperidine

[0540] Prepared from the product of Example 16 and piperidine.

[0541]¹H NMR (400 MHz, CDCl₃): 7.19 (d, J=8.6 Hz, 2H), 6.89 (d, J=8.6Hz, 2H), 3.65 (d, J=12.1 Hz, 2H), 3.53 (s, 2H), 2.65 (ddd, J=12.2, 12.2,2.3 Hz, 2H), 2.50-2.45 (m, 4H), 2.37-2.29 (br s, 2H), 2.16 (d, J=7.3 Hz,2H), 1.88-1.74 (m, 6H), 1.68-1.53 (m, 7H), 1.46-1.39 (m, 2H), 1.33(dddd, J=12.2, 12.2, 12.2, 3.8 Hz, 2H).

Example 31

[0542]

[0543]4-{1-(4-Pyrrolidin-1-ylmethyl-phenyl)-pieridin-4-ylmethyl}-morpholine

[0544] Prepared from the product of Example 16 and morpholine.

[0545]¹H NMR (400 MHz, CDCl₃): 7.20 (d, J=8.6 Hz, 2H), 6.89 (d, J=8.6Hz, 2H), 3.71 (t, J=4.7 Hz, 4H), 3.66 (d, J=12.2 Hz, 2H), 3.53 (s, 2H),2.69-2.63 (m, 2H), 2.48 (br s, 4H), 2.43-2.41 (m, 4H), 2.22 (d, J=7.1Hz, 2H), 1.86 (d, J=12.4 Hz, 2H), 1.78-1.73 (m, 4H), 1.67-1.59 (m, 1H),1.39-1.29 (m, 2H).

Example 32

[0546]

[0547]4-{3-(4-Pyrrolidin-1-vimethyl-piperidin-1-yl)-benzyl}-thiomorpholine

[0548] Prepared from the product of Example 20 and thiomorpholine.

[0549]¹H NMR (400 MHz, CDCl₃): 7.21-7.17 (m, 1H), 6.90 (s, 1H),6.85-6.76 (m, 2H), 3.69 (d, J=12.3 Hz, 2H), 3.46 (s, 2H), 2.71-2.66 (m,10H), 2.50 (br s, 4H), 2.36 (d, J=7.1 Hz, 2H), 1.90 (d, J=12.8 Hz, 2H),1.82-1.75 (m, 4H), 1.62-1.57 (m, 1H), 1.42-1.32 (m, 2H).

Example 33

[0550]

[0551] 4-{3-(4-Pyrrolidin-1-ylmethyl-piperidin-1-yl)-benzyl}-morpholine

[0552] Prepared from the product of Example 20 and morpholine.

[0553]¹H NMR (400 MHz, CDCl₃): 7.21-7.17 (m, 1H), 6.92 (s, 1H),6.85-6.78 (m, 2H), 3.72-3.67 (m, 6H), 3.45 (s, 2H), 2.72-2.65 (m, 2H),2.49-2.44 (m, 8H), 2.36 (d, J=7.1 Hz, 2H), 1.90 (d, J=12.8 Hz, 2H),1.82-1.75 (m, 4H), 1.67-1.58 (m, 1H), 1.42-1.32 (m, 2H).

Example 34

[0554]

[0555]4-Pyrrolidin-1-ylmethyl-1-(3-pyrrolidin-1-ylmethyl-phenyl)-piperidine

[0556] Prepared from the product of Example 20 and pyrrolidine.

[0557]¹H NMR (400 MHz, CDCl₃): 7.20-7.16 (m, 1H), 6.93 (s, 1H),6.84-6.78 (m, 2H), 3.69 (d, J=12.2 Hz, 2H), 3.57 (s, 2H), 2.71-2.64 (m,2H), 2.50-2.49 (m, 8H), 2.35 (d, J=7.2 Hz, 2H), 1.88 (d, J=13.1 Hz, 2H),1.79-1.57 (m, 9H), 1.41-1.25 (m, 2H).

Example 35

[0558]

[0559] 1-{3-(4-pyrrolidin-1-ylmethyl-piperidin-1-yl)-benzyl}-piperidine

[0560] Prepared from the product of Example 20 and piperidine.

[0561]¹H NMR (400 MHz, CDCl₃): 7.20-7.16 (m, 1H), 6.92 (s, 1H),6.84-6.77 (m, 2H), 3.69 (d, J=12.3 Hz, 2H), 3.42 (s, 2H), 2.73-2.34 (m,12H), 1.89 (d, J=12.9 Hz, 2H), 1.82-1.32 (m, 9H).

Example 36

[0562]

[0563]1-{4-(4-Pyrrolidin-1-ylmethyl-piperidin-1-yl)-benzyl}-azacyclotridecane

[0564] Prepared from the product of Example 9 and dodecamethyleneamine.

[0565]¹H NMR (400 MHz, CDCl₃): 7.19 (d, J=8.4 Hz, 2H), 6.89 (d, J=8.6Hz, 2H), 3.67 (d, J=12.2 Hz, 2H), 3.39 (s, 2H), 2.69-2.63 (m, 4H), 2.49(br s, 4H), 2.37-2.31 (m, 6H), 1.89 (d, J=12.1 Hz, 2H), 1.79-1.77 (m,4H), 1.63-1.35 (m, 21H).

Example 37

[0566]

[0567]Cyclohexyl-{4-(4-pyrrolidin-1-ylmethyl-piperidin-1-yl)-benzyl}-amine

[0568] Prepared from the product of Example 9 and cyclohexylamine.

[0569]¹H NMR (400 MHz, CDCl₃): 7.18 (d, J=8.5 Hz, 2H), 6.90 (d, J=8.6Hz, 2H), 3.71 (s, 2H), 3.66 (d, J=12.3 Hz, 2H), 2.69-2.63 (m, 2H),2.50-2.46 (m, 5H), 2.35 (d, J=7.2 Hz, 2H), 1.90-1.59 (m, 11H), 1.39-1.12(m, 8H).

Example 38

[0570]

[0571]1-{4-(4-Pyrrolidin-1-ylmethyl-piperidin-1-yl)-benzyl}-piperidin-4-ol

[0572] Prepared from the product of Example 9 and 4-hydroxypiperidine.

[0573]¹H NMR (400 MHz, CDCl₃): 7.26-7.15 (m, 2H), 6.88 (d, J=8.5 Hz,2H), 3.68-3.65 (m, 3H), 3.41 (s, 2H), 2.75-2.64 (m, 4H), 2.49-2.47 (m,4H), 2.35 (d, J=7.1 Hz, 2H), 2.10 (t, J=9.0 Hz, 2H), 1.90-1.75 (m, 10H),1.65-1.52 (m, 2H), 1.41-1.31 (m, 2H).

Example 39

[0574]

[0575]1-Methyl-4-{4-(4-pyrrolidin-1-ylmethyl-piperidin-1-yl)-benzyl}-piperazine

[0576] Prepared from the product of Example 9 and N-methylpiperazine.

[0577]¹H NMR (400 MHz, CDCl₃): 7.17 (d, J=8.5 Hz, 2H), 6.89 (d, J=8.6Hz, 2H), 3.66 (d, J=12.2 Hz, 2H), 3.42 (s, 2H), 2.73-2.31 (m, 14H), 2.27(s, 3H), 1.88 (br s, 4H), 1.82-1.75 (m, 4H), 1.65-1.57 (m, 1H),1.41-1.31 (m, 2H).

Example 40

[0578]

[0579]4-{4-(4-Pyrrolidin-1-ylmethyl-piperidin-1-yl)-benzyl}-thiomorpholine

[0580] Prepared from the product of Example 9 and thiomorpholine.

[0581]¹H NMR (400 MHz, CDCl₃): 7.15 (d, J=8.5 Hz, 2H), 6.89 (d, J=8.6Hz, 2H), 3.67 (d, J=12.2 Hz, 2H), 3.43 (s, 2H), 2.73-2.59 (m, 10H), 2.49(br s, 4H), 2.36 (d, J=7.2 Hz, 2H), 1.88 (d, J=13.3 Hz, 2H), 1.80-1.75(m, 4H), 1.67-1.57 (m, 1H), 1.41-1.31 (m, 2H).

Example 41

[0582]

[0583] 4-{4-(4-Pyrrolidin-1-ylmethyl-piperidin-1-yl)-benzyl}-morpholine

[0584] Prepared from the product of Example 9 and morpholine.

[0585]¹H NMR (400 MHz, CDCl₃): 7.18 (d, J=8.5 Hz, 2H), 6.89 (d, J=8.3Hz, 2H), 3.71-3.65 (m, 6H), 3.40 (s, 2H), 2.73-2.61 (m, 2H), 2.49 (br s,4H), 2.42 (bs, 4H), 2.36 (d, J=7.2 Hz, 2H), 1.88 (d, J=12.3 Hz, 2H),1.80-1.75 (m, 4H), 1.66-1.57 (m, 1H), 1.41-1.31 (m, 2H).

Example 42

[0586]

[0587]Dimethyl-{4-(4-pyrrolidin-1-ylmethyl-piperidin-1-yl)-benzyl}-amine

[0588] Prepared from the product of Example 9 and dimethylaminehydrochloride.

[0589]¹H NMR (400 MHz, CDCl₃): 7.16 (d, J=8.6 Hz, 2H), 6.91-6.88 (m,2H), 3.67 (d, J=11.2 Hz, 2H), 3.33 (s, 2H), 2.70-2.64 (m, 2H), 2.52-2.47(m, 4H), 2.35 (d, J=7.1 Hz, 2H), 2.21 (s, 6H), 1.89 (d, J=12.9 Hz, 2H),1.82-1.76 (m, 4H), 1.65-1.56 (m, 1H), 1.42-1.32 (m, 2H).

Example 43

[0590]

[0591] 4-{2-(4-Pyrrolidin-1-ylmethyl-piperidin-1-yl)-benzyl}-morpholine

[0592] Prepared from the product of Example 17 and pyrrolidine.

[0593]¹H NMR (400 MHz, CDCl₃): 7.40 (dd, J=7.4, 1.6 Hz, 1H), 7.21 (dd,J=7.8, 1.5 Hz, 2H), 7.06 (dd, J=8.0, 1.0 Hz, 1H), 7.02 (dd, J=7.4, 1.7Hz, 1H), 3.67 (t, J=4.7 Hz, 4H), 3.54 (s, 2H), 3.24-3.17 (m, 2H), 2.64(ddd, J=11.7, 11.7, 2.1 Hz, 2H), 2.55-2.45 (m, 8H), 2.40 (m, 7.3 Hz,2H), 1.90-1.77 (m, 6H), 1.67-1.55 (m, 1H), 1.45-1.33 (m, 2H).

Example 44

[0594]

[0595]4-{1-(4-Piperidin-1-ylmethyl-phenyl)-piperidin-4-ylmethyl}-morpholine

[0596] Prepared from the product of Example 15 and morpholine.

[0597]¹H NMR (400 MHz, CDCl₃): 7.18 (d, J=8.5 Hz, 2H), 6.88 (d, J=8.6Hz, 2H), 3.71 (t, J=4.7 Hz, 4H), 3.66 (d, J=12.3 Hz, 2H), 3.39 (s, 2H),2.69-2.63 (m, 2H), 2.43-2.41 (m, 4H), 2.36 (br s, 4H), 2.22 (d, J=7.2Hz, 2H), 1.85 (d, J=12.7 Hz, 2H), 1.66-1.53 (m, 5H), 1.42-1.29 (m, 4H).

Example 45

[0598]

[0599] 1-{4-(4-Pyrrolidin-1-ylmethyl-piperidin-1-yl)-benzyl}-piperidine

[0600] Prepared from the product of Example 15 and pyrrolidine.

[0601]¹H NMR (400 MHz, CDCl₃): 7.17 (d, J=8.6 Hz, 2H), 6.88 (d, J=8.8Hz, 2H), 3.66 (d, J=12.3 Hz, 2H), 3.39 (s, 2H), 2.66 (ddd, J=12.2, 12.2,2.5 Hz, 2H), 2.51-2.46 (m, 4H), 2.37-2.31 (m, 6H), 1.91-1.85 (m, 2H),1.81-1.75 (m, 4H), 1.65-1.52 (m, 5H), 1.45-1.31 (m, 4H).

Example 46

[0602]

[0603]Cyclohexyl-{1-(4-morpholin-4-ylmethyl-phenyl)-piperidin-4-yl}-amine

[0604] Prepared from the product of Example 18 and cyclohexylamine.

[0605]¹H NMR (400 MHz, CDCl₃): 7.17 (d, J=8.6 Hz, 2H), 6.87 (d, J=8.8Hz, 2H), 3.71-3.61 (m, 6H), 3.40 (s, 2H), 2.78-2.70 (m, 3H), 2.65-2.55(m, 1H), 2.44-2.38 (m, 4H), 1.99-1.83 (m, 4H), 1.77-1.70 (m, 2H),1.66-1.59 (m, 1H), 1.51-1.39 (m, 2H), 1.32-1.01 (m, 6H).

Example 47

[0606]

[0607]Cyclohexyl-methyl-{1-(4-morpholin-4-ylmethyl-phenyl)-piperidin-4-yl}-amine

[0608] Prepared from the product of Example 18 andN-methyl-N-cyclohexylamine.

[0609]¹H NMR (400 MHz, CDCl₃): 7.19 (d, J=8.8 Hz, 2H), 6.88 (d, J=8.8Hz, 2H), 3.75-3.67 (m, 6H), 3.41 (s, 2H), 2.73-2.53 (m, 4H), 2.45-2.38(m, 4H), 2.28 (s, 3H), 1.89-1.59 (m, 9H), 1.35-1.19 (m, 4H), 1.16-1.04(m, 1H).

Example 48

[0610]

[0611]4-{4-{4-(4-Methyl-piperazin-1-yl)-piperidin-1-yl}-benzyl}-morpholine

[0612] Prepared from the product of Example 19 and N-methylpiperazine.

[0613]¹H NMR (400 MHz, CDCl₃): 7.17 (d, J=8.6 Hz, 2H), 6.87 (d, J=8.6Hz, 2H), 3.76-3.66 (m, 6H), 3.40 (s, 2H), 2.69 (ddd, J=12.3, 12.3, 2.3Hz, 2H), 2.65-2.45 (m, 6H), 2.44-2.31 (m, 7H), 2.29 (s, 3H), 1.97-1.90(m, 2H), 1.72-1.60 (m, 2H).

Example 49

[0614]

[0615]Ethyl-methyl-{1-(4-morpholin-4-ylmethyl-phenyl)-piperidin-4-yl}-amine

[0616] Prepared from the product of Example 19 and N-methylethylamine.

[0617]¹H NMR (400 MHz, CDCl₃): 7.18 (d, J=8.8 Hz, 2H), 6.88 (d, J=8.8Hz, 2H), 3.76-3.67 (m, 6H), 3.49 (s, 3H), 3.41 (s, 2H), 2.68 (ddd,J=12.3, 12.3, 2.4 Hz, 2H), 2.57 (q, J=7.3 Hz, 2H), 2.54-2.46 (m, 1H),2.45-2.40 (m, 4H), 1.90-1.84 (m, 2H), 1.74-1.62 (m, 2H), 1.08 (t, J=7.2Hz, 3H).

Example 50

[0618]

[0619] 4-{1-(4-Morpholin-4-ylmethyl-phenyl)-piperidin-4-yl}-morpholine

[0620] Prepared from the product of Example 19 and morpholine.

[0621]¹H NMR (400 MHz, CDCl₃): 7.19 (d, J=8.6 Hz, 2H), 6.89 (d, J=8.8Hz, 2H), 3.76-3.67 (m, 10H), 3.41 (s, 2H), 2.71 (ddd, J=12.2, 12.2, 2.4Hz, 2H), 2.61-2.56 (m, 4H), 2.45-2.39 (m, 4H), 2.36-2.27 (m, 1H),1.98-1.90 (m, 2H), 1.71-1.60 (m, 2H).

Example 51

[0622]

[0623] 4-{4-(4-Pyrrolidin-1-yl-pieridin-1-yl)-benzyl}-morpholine

[0624] Prepared from the product of Example 19 and pyrrolidine.

[0625]¹H NMR (400 MHz, CDCl₃): 7.17 (d, J=8.6 Hz, 2H), 6.88 (d, J=8.6Hz, 2H), 3.71-3.64 (m, 6H), 3.40 (s, 2H), 2.73 (ddd, J=12.3, 2.5 Hz,2H), 2.62-2.57 (m, 4H), 2.44-2.37 (m, 4H), 2.15-2.06 (m, 1H), 2.02-1.95(m, 2H), 1.82-1.77 (m, 4H), 1.72-1.61 (m, 2H).

Example 52

[0626]

[0627] 1′-(4-Morpholin-4-ylmethyl-phenyl)-{1,4′}bipiperidinyl

[0628] Prepared from the product of Example 19 and piperidine.

[0629]¹H NMR (400 MHz, CDCl₃): 7.17 (d, J=8.8 Hz, 2H), 6.88 (d, J=8.8Hz, 2H), 3.77-3.67 (m, 6H), 3.41 (s, 2H), 2.67 (ddd, J=12.3, 12.3, 2.4Hz, 2H), 2.56-2.51 (m, 4H), 2.44-2.33 (m, 5H), 1.94-1.87 (m, 2H),1.75-1.57 (m, 6H), 1.48-1.41 (m, 2H).

Example 53

[0630]

[0631] 1′-(4-Piperidin-1-ylmethyl-phenyl)-{1,4′}bipiperidinyl

[0632] Prepared from the product of Example 5 and piperidine.

[0633]¹H NMR (400 MHz, CDCl₃): 7.18 (m, 2H), 6.88 (m, 2H), 3.65 (m, 2H),3.51 (s, 2H), 2.65 (m, 2H), 2.50-2.44 (m, 8H), 2.34 (d, J=7.1 Hz, 2H),1.87 (br m, 2H), 1.81-1.71 (m, 8H), 1.65-1.53 (m, 1H), 1.41-1.30 (m,2H).

Example 54

[0634]

[0635] (4-{1,4′}Bipiperidinyl-1′-yl-benzyl)-pyridin-2-yl-amine Asolution of the product of Example 5 (109 mg), 2-aminopyridine (45 mg),and acetic acid (0.05 mL) in DCE (1 mL) was treated with sodiumtriacetoxyborohydride (127 mg). After 16 h, the resulting mixture wastreated with 10% potassium hydroxide (1 mL), and extracted with DCM (2×1mL). The combined organic phases were dried (MgSO₄) and chromatographedon silica gel (0-8% 2 M methanolic ammonia/DCM), giving the titlecompound (83 mg).

[0636]¹H NMR (400 MHz, CDCl₃): 8.10 (ddd, J=4.9, 1.8, 0.8 Hz, 1H), 7.39(ddd, J=8.8, 7.0, 2.0 Hz, 1H), 7.23 (d, J=8.6 Hz, 2H), 6.90 (d, J=8.8Hz, 2H), 6.57 (ddd, J=7.3, 5.1, 0.8 Hz, 1H), 6.37 (d, J=8.4 Hz, 1H),4.77-4.71 (m, 1H), 4.39 (d, J=5.5 Hz, 2H), 3.76-3.70 (m, 2H), 2.68 (ddd,J=12.3, 12.3, 2.4 Hz, 2H), 2.56-2.51 (m, 4H), 2.42-2.34 (m, 1H),1.94-1.87 (m, 2H), 1.74-1.56 (m, 6H), 1.47-1.41 (m, 2H).

[0637] The compounds of Example 55 through Example 59 were preparedaccording to the procedure of Example 54 using the specified carbonylcompound and aminoarene.

Example 55

[0638]

[0639]Phenyl-{1-(4-pyrrolidin-1-ylmethyl-phenyl)-piperidin-4-ylmethyl}-amine

[0640] Prepared from the product of Example 16 and aniline.

[0641]¹H NMR (400 MHz, CDCl₃): 7.21-7.16 (m, 4H), 6.89 (d, J=8.6 Hz,2H), 6.71-6.61 (m, 3H), 3.75-3.67 (m, 3H), 3.53 (s, 2H), 3.08-3.06 (m,2H), 2.72-2.65 (m, 2H), 2.48 (br s, 4H), 1.90 (d, J=12.3 Hz, 2H),1.78-1.67 (m, 5H), 1.50-1.40 (m, 2H).

Example 56

[0642]

[0643]Pyridin-2-yl-{1-(4-pyrrolidin-1-ylmethyl-phenyl)-piperidin-4-ylmethyl}-amine

[0644] Prepared from the product of Example 16 and 2-aminopyridine.

[0645]¹H NMR (400 MHz, CDCl₃): 8.09-8.07 (m, 1H), 7.44-7.39 (m, 1H),7.20 (d, J=8.6 Hz, 2H), 6.91-6.88 (m, 2H), 6.58-6.55 (m, 1H), 6.39 (d,J=8.5 Hz, 2H), 4.57 (brs, 1H), 3.69 (d, J=12.2 Hz, 2H), 3.53 (s, 2H),3.22 (t, J=6.5 Hz, 2H), 2.72-2.65 (m, 2H), 2.50-2.47 (m, 4H), 1.92-1.70(m, 5H), 1.50-1.40 (m, 2H).

Example 57

[0646]

[0647]1-{1-(4-Piperidin-1-ylmethyl-phenyl)-piperidin-4-ylmethyl}-piperidine

[0648] A solution of the product of Example 21 (194.6 mg), piperidine(196 μL), and acetic acid (114 μL) in DCM (5 mL) was treated with sodiumtriacetoxyborohydride (570 mg). After 16 h, the resulting mixture wastreated with 10% sodium hydroxide (10 mL), and the mixture was extractedwith DCM (3×10 mL). The combined organic phases were dried (sodiumsulfate) and concentrated under reduced pressure. Chromatography of theresidue on silica gel (1-7% 2 M methanolic ammonia/DCM) gave the titlecompound (193.1 mg).

[0649]¹H NMR (400 MHz, CDCl₃): 7.16 (m, 2H), 6.87 (m, 2H), 3.73 (m, 2H),3.39 (s, 2H), 2.70-2.65 (m, 2H), 2.57-2.49 (br m, 4H), 2.41-2.29 (br,5H), 1.94-1.86 (br m, 2H), 1.75-1.51 (m, 10H), 1.48-1.37 (br m, 4H).

Example 58

[0650]

[0651]4-Pyrrolidin-1-ylmethyl-1-(4-pyrrolidin-1-ylmethyl-phenyl)-piperidine Asolution of the product of Example 21 (185.5 mg), pyrrolidine (160 μL),and acetic acid (114 μL) in DCM (5 mL) was treated with sodiumtriacetoxyborohydride (570 mg). After 16 h, the resulting mixture wastreated with 10% sodium hydroxide (10 mL), and the mixture was extractedwith DCM (3×10 mL). The combined organic phases were dried (sodiumsulfate) and concentrated under reduced pressure. Chromatography of theresidue on silica gel (1-7% 2 M methanolic ammonia/DCM) gave the titlecompound (114.1 mg).

[0652]¹H NMR (400 MHz, CDCl₃): 7.17 (m, 2H), 6.88 (m, 2H), 3.65 (m, 2H),3.38 (s, 2H), 2.65 (m, 2H), 2.39-2.28 (br m, 8H), 2.16 (d, J=7.1 Hz, 2H)1.84 (br m, 2H), 1.69-1.52 (m, 9H) 1.46-1.26 (m, 6H).

Example 59

[0653]

[0654](4-Fluoro-phenyl)-{4-(4-pyrrolidin-1-ylmethyl-piperidin-1-yl)-benzyl}-amine

[0655] Prepared from the product of Example 9 and 4-fluoroaniline.

[0656]¹H NMR (400 MHz, CDCl₃): 7.23 (d, J=8.5 Hz, 2H), 6.92-6.84 (m,4H), 6.58-6.55 (m, 2H), 4.17 (d, J=2.4 Hz, 2H), 3.80 (br s, 1H), 3.68(d, J=12.3 Hz, 2H), 2.71-2.65 (m, 2H), 2.49 (br s, 4H), 2.35 (d, J=7.2Hz, 2H), 1.88 (d, J=12.7 Hz, 2H), 1.82-1.77 (m, 4H), 1.65-1.57 (m, 1H),1.42-1.31 (m, 2H).

Example 60

[0657]

[0658]4-{2-{1-(4-Piperidin-1-ylmethyl-phenyl)-pyrrolidin-3-yl}-ethyl}-morpholine

[0659] A solution of the product of the product of Example 10 (144 mg),morpholine (0.05 mL), N-ethyl-N,N-diisopropylamine (0.17 mL), andtrimethyl-(cyanomethyl)phosphonium iodide (243 mg) in propionitrile (1mL) was heated in a 90° C. bath for 2 h. The resulting mixture wascooled to room temperature, treated with 10% aqueous potassium hydroxide(2 mL), and extracted with DCM (3×2 mL). The combined extracts weredried (MgSO₄) and chromatographed on silica gel (0-10% 2 M methanolicammonia/DCM), giving the title compound as a yellow oil (113 mg).

[0660]¹H NMR (400 MHz, CDCl₃): 7.14 (d, J=8.4 Hz, 2H), 6.48 (d, J=8.6Hz, 2H), 3.73 (t, J=4.7 Hz, 4H), 3.45 (dd, J=8.8, 7.6 Hz, 1H), 3.39 (s,2H), 3.35 (ddd, J=9.0, 9.0, 3.1 Hz, 1H), 3.27 (ddd, J=8.8, 8.8, 7.0 Hz,1H), 2.91 (dd, J=8.4, 8.4 Hz, 1H), 2.49-2.24 (m, 11H), 2.19-2.10 (m,1H), 1.70-1.53 (m, 7H), 1.45-1.37 (m, 2H).

[0661] The compounds of Example 61 and Example 62 were preparedaccording to the procedure of Example 54 using the specified alcohol andsecondary amine.

Example 61

[0662]

[0663]Diethyl-{2-{1-(4-piperidin-1-vimethyl-phenyl)-pyrrolidin-3-yl}-ethyl}-amine

[0664] Prepared from the product of Example 10 and diethylamine.

[0665]¹H NMR (400 MHz, CDCl₃): 7.12 (d, J=8.4 Hz, 2H), 6.49 (d, J=8.6Hz, 2H), 3.45 (dd, J=8.2, 8.0 Hz, 1H), 3.34 (ddd, J=9.0, 9.0, 3.1 Hz,1H), 3.27 (ddd, J=9.0, 9.0, 6.9 Hz, 1H), 2.90 (dd, J=8.5, 8.5 Hz, 1H),2.57-2.46 (m, 6H), 2.40-2.31 (m, 4H), 2.30-2.22 (m, 2H), 2.19-2.11 (m,1H), 1.69-1.52 (m, 8H), 1.45-1.37 (m, 2H), 1.03 (t, J=7.1 Hz, 6H).

Example 62

[0666]

[0667]Methyl-phenethyl-{2-{1-(4-piperidin-1-ylmethyl-phenyl)-pyrrolidin-3-yl}-ethyl}-amine

[0668] Prepared from the product of Example 10 andN-methylphenethylamine.

[0669]¹H NMR (400 MHz, CDCl₃): 7.31-7.26 (m, 2H), 7.23-7.19 (m, 3H),7.14 (d, J=8.6 Hz, 2H), 6.48 (d, J=8.6 Hz, 2H), 3.43 (dd, J=8.8, 7.6 Hz,1H), 3.34 (ddd, J=9.0, 9.0, 3.1 Hz, 1H), 3.26 (ddd, J=8.8, 8.8, 6.8 Hz,1H), 2.89 (dd, J=8.5, 8.5 Hz, 1H), 2.81-2.76 (m, 2H), 2.65-2.59 (m, 2H),2.46 (ddd, J=8.4, 7.3, 2.2 Hz, 2H), 2.46-2.32 (m, 4H), 2.32 (s, 3H),2.31-2.20 (m, 2H), 2.17-2.08 (m, 1H), 1.68-1.52 (m, 8H), 1.45-1.37 (m,2H).

[0670] The compounds of Example 63 through Example 67 were preparedaccording to the procedure of Example 6 using the specifiedfluorobenzaldehyde.

Example 63

[0671]

[0672]4-(4-Pyrrolidin-1-vimethyl-piperidin-1-yl)-3-trifluoromethyl-benzaldehyde

[0673] Prepared from the product of Example 4 and4-fluoro-3-trifluoromethyl-benzaldehyde.

Example 64

[0674]

[0675] 3-Nitro-4-(4-pyrrolidin-1-ylmethyl-piperidin-1-yl)-benzaldehyde

[0676] Prepared from the product of Example 4 and4-fluoro-3-nitro-benzaldehyde.

Example 65

[0677]

[0678]4-(4-Pyrrolidin-1-ylmethyl-piperidin-1-yl)-2-trifluoromethyl-benzaldehyde

[0679] Prepared from the product of Example 4 and4-fluoro-2-trifluoromethyl-benzaldehyde.

Example 66

[0680]

[0681] 3-Methyl-4-(4-pyrrolidin-1-ylmethyl-piperidin-1-yl)-benzaldehyde

[0682] Prepared from the product of Example 4 and4-fluoro-3-methyl-benzaldehyde.

Example 67

[0683]

[0684] 3-Fluoro-4-(4-pyrrolidin-1-ylmethyl-piperidin-1-yl)-benzaldehyde

[0685] Prepared from the product of Example 4 and3,4-difluorobenzaldehyde.

[0686] The compounds of Example 68 through 81 were prepared according tothe procedure of Example 22 from the specified carbonyl compound andamine.

Example 68

[0687]

[0688]1-[4-(4-Pyrrolidin-1-ylmethyl-piperidin-1-yl)-3-trifluoromethyl-benzyl]-piperidine

[0689] Prepared from the product of Example 63 and piperidine.

[0690]¹H NMR (400 MHz, CDCl₃): 7.43 (d, J=1.9 Hz, 1H), 7.35 (dd, J=8.2,1.6 Hz, 1H), 7.17 (d, J=8.4 Hz, 1H), 3.34 (s, 2H), 2.97 (d, J=11.5 Hz,2H), 2.59 (tt, J=11.3, 2.0 Hz, 2H), 2.48-2.40 (m, 4H), 2.33-2.22 (m,6H), 1.77-1.66 (m, 6H), 1.55-1.43 (m, 5H), 1.39-1.26 (m, 4H).

Example 69

[0691]

[0692]1-(2-Nitro-4-pyrrolidin-1-ylmethyl-phenyl)-4-pyrrolidin-1-ylmethyl-piperidine

[0693] Prepared from the product of Example 64 and piperidine.

[0694]¹H NMR (400 MHz, CDCl₃): 7.68 (d, J=2.0, 1H), 7.4 (dd, J=8.4, 2.2Hz, 1H), 7.06 (d, 8.4 Hz, 1H), 3.40 (s, 2H), 3.26 (d, J=12.3 Hz, 2H),2.79 (tt, J=11.9, 2.2 Hz, 2H), 2.54-2.44 (m, 4H), 2.42-2.26 (m, 6H),1.88-1.74 (m, 6H), 1.6-1.5 (m, 5H), 1.48-1.36 (m, 4H).

Example 70

[0695]

[0696]4-[3-Nitro-4-(4-pyrrolidin-1-ylmethyl-piperidin-1-yl)-benzyl]-morpholine

[0697] Prepared from the product of Example 64 and morpholine.

[0698]¹H NMR (400 MHz, CDCl₃): 7.71 (d, J=2.0 Hz, 1H), 7.74 (dd, J=8.4,2.2 Hz, 1H), 7.06 (d, J=8.6, 1H), 3.69 (t, J=4.5 Hz, 4H), 3.43 (s, 2H),3.26 (d, J=12.3, 2H), 2.79 (tt, J=12.0, 2.1 Hz, 2H), 2.54-2.45 (m, 4H),2.45-2.39 (m, 4H), 2.39-2.32 (m, 2H), 1.88-1.72 (m, 6H), 1.68-1.34 (m,1H), 1.48-1.34 (m, 2H).

Example 71

[0699]

[0700]1-[3-Nitro-4-(4-pyrrolidin-1-vimethyl-piperidin-1-yl)-benzyl]-piperidin-4-ol

[0701] Prepared from the product of Example 64 and 4-hydroxypiperidine.

[0702]¹H NMR (400 MHz, CDCl₃): 7.69 (d, J=2.0 Hz, 1H), 7.40 (dd, J=8.4,2.1 Hz, 1H), 7.07 (d, J=8.4 Hz, 1H), 3.70 (m, 1H), 3.43 (s, 2H), 3.26(d, J=12.0 Hz, 2H), 2.79 (tt, J=12.0, 2.4 Hz, 2H), 2.73-2.70 (m, 2H),2.50-2.45 (m, 4H), 2.36 (d, J=6.8 Hz, 2H), 2.14 (t, J=10.4 Hz, 2H),1.90-1.75 (m, 8H), 1.62-1.54 (m, 4H), 1.46-1.39 (m, 2H).

Example 72

[0703]

[0704]1-[4-(4-Pyrrolidin-1-ylmethyl-piperidin-1-yl)-2-trifluoromethyl-benzyl]-piperidine

[0705] Prepared from the product of Example 65 and 4-hydroxypiperidine.

[0706]¹H NMR (400 MHz, CDCl₃): 7.60 (d, J=8.6 Hz, 1H), 7.13 (d, J=2.6Hz, 1H), 7.04 (dd, J=8.6, 2.5 Hz, 1H), 3.68 (d, J=12.3 Hz, 2H), 3.66 (s,2H), 2.70 (tt, J=12.2, 2.5 Hz, 2H), 2.5-2.48 (m, 4H), 2.4-2.3 (m, 6H),1.91 (d, J=1.1, 2H), 1.85-1.70 (m, 4H), 1.70-1.50 (m, 5H), 1.50-1.20 (m,4H).

Example 73

[0707]

[0708]1-Isopropyl-4-[3-methyl-4-(4-pyrrolidin-1-ylmethyl-piperidin-1-yl)-benzyl]-piperazine

[0709] Prepared from the product of Example 66 and1-isopropylpiperazine.

[0710]¹H NMR (400 MHz, CDCl₃): 7.10 (d, J=1.6 Hz, 1H), 7.06 (dd, J=8.0,1.9 Hz, 1H), 6.93 (d, J=8.0 Hz, 1H), 3.42 (s, 2H), 3.10 (d, J=9.1 Hz,2H), 2.7-2.2 (m, 15H), 2.1-1.7 (m, 11H), 1.66-1.53 (m, 1H), 1.5-1.3 (m,2H), 1.04 (d, J=6.5 Hz, 6H).

Example 74

[0711]

[0712]1-(2-Methyl-4-pyrrolidin-1-ylmethyl-phenyl)-4-pyrrolidin-1-vimethyl-pyrrolidine

[0713] Prepared from the product of Example 66 and pyrrolidine.

[0714]¹H NMR (400 MHz, CDCl₃): 7.13 (d, J=2.0 Hz, 1H), 7.07 (dd, J=8.2,2.0 Hz, 1H), 6.93 (d, J=8.2 Hz, 1H), 3.52 (s, 2H), 3.10 (d, J=12.1, 2H),2.59 (tt, J=12.1, 2.2 Hz, 2H), 2.54-2.44 (m, 8H), 2.41-2.37 (m, 2H),2.26 (s, 3H), 1.89-1-81 (m, 2H), 1.81-1.72 (m, 8H), 1.65-1.52 (m, 1H),1.45-1.31 (m, 2H).

Example 75

[0715]

[0716]1-[3-Methyl-4-(4-pyrrolidin-1-ylmethyl-piperidin-1-yl)-benzyl]-pyrrolidine

[0717] Prepared from the product of Example 66 and piperidine.

[0718]¹H NMR (400 MHz, CDCl₃): 7.10 (d, J=1.8 Hz, 1H), 7.06 (dd, J=8.0,1.8 Hz, 1H), 6.93 (d, J=8.0 Hz, 1H), 3.38 (s, 2H), 3.11 (d, 2H),2.65-2.54 (m, 2H), 2.54-2.43 (m, 4H), 2.42-2.29 (m, 6H), 2.27 (s, 3H),1, 90-1.81 (m, 2H), 1.81-1.71 (m, 4H), 1.66-1.50 (m, 5H), 1.47-1.31 (m,4H).

Example 76

[0719]

[0720]1-{1-[4-(4-Pyrrolidin-1-yl-piperidin-1-ylmethyl)-2-trifluoromethyl-phenyl]-piperidin-4-ylmethyl}-pyrrolidine

[0721] Prepared from the product of Example 63 and4-N-pyrrolidinylpiperidine.

[0722]¹H NMR (400 MHz, CDCl₃): 7.52 (d, J=1.5 Hz, 1H), 7.44 (d, J=8.2Hz, 1H), 7.28-7.25 (m, 1H), 3.45 (s, 2H), 3.05 (d, J=11.4 Hz, 2H), 2.84(d, J=11.7 Hz, 2H), 2.68 (t, J=11.3 Hz, 2H), 2.63-2.44 (m, 8H), 2.38 (d,J=7.0, 2H), 2.10-1.91 (m, 3H), 1.91-1.70 (m, 12H), 1.49-1.33 (m, 2H).

Example 77

[0723]

[0724]1-(1-{3-Trifluoromethyl-4-[4-(4-trifluoromethyl-phenyl)-piperidin-1-ylmethyl]-phenyl}-piperidin-4-ylmethyl)-pyrrolidine

[0725] Prepared from the product of Example 65 and4-(4-trifluouromethylphenyl)-piperidine.

[0726]¹H NMR (500 MHz, CDCl₃): 7.62 (d, J=8.6 Hz, 1H), 7.54 (d, J=8.0Hz, 2H), 7.34 (d, J=8.2 Hz, 2H), 7.14 (d, J=2.5 Hz, 1H), 7.01 (dd,J=8.1, 2.5 Hz, 1H), 3.70 (d, J=12.3 Hz, 2H), 3.58 (s, 2H), 2.98 (d,J=11.7 Hz, 2H), 2.88-2.34 (m, 8H), 2.31-1.56 (m, 13H), 1.52-1.05 (m,3H).

Example 78

[0727]

[0728]1-{1-[2-Fluoro-4-(4-phenyl-piperidin-1-ylmethyl)-phenyl]-piperidin-4-ylmethyl}-pyrrolidine

[0729] Prepared from the product of Example 67 and 4-phenylpiperidine.

[0730]¹H NMR (500 MHz, CDCl₃): 7.37-7.16 (m, 5H), 7.12-6.87 (m, 3H),3.53-3.41 (m, 4H), 3.01 (d, J=11.5 Hz, 2H), 2.67 (t, J=11.5, 9.9 Hz,2H), 2.58-2.45 (m, 5H), 2.40 (d, J=7.1, 2H), 2.14-2.01 (m, 2H),1.97-1.87 (m, 2H), 1.86-1.73 (m, 8H), 1.69-1.56 (m, 1H), 1.54-1.41 (m,2H).

Example 79

[0731]

[0732][3-Fluoro-4-(4-pyrrolidin-1-ylmethyl-piperidin-1-yl)-benzyl]-dimethyl-amine

[0733] Prepared from the product of Example 67 and dimethylaminehydrochloride.

[0734]¹H NMR (500 MHz, CDCl₃): 7.00-6.93 (m, 2H), 6.90-6.87 (m, 1H),3.46-3.40 (m, 2H), 3.33 (s, 2H), 2.67-2.59 (m, 2H), 2.57-2.54 (m, 4H),2.38 (d, J=7.1 Hz, 2H), 2.21 (s, 6H), 1.91-1.84 (m, 2H), 1.81-1.75 (m,4H), 1.66-1.55 (m, 1H), 1.49-1.38 (m, 2H).

Example 80

[0735]

[0736]1-[3-Fluoro-4-(4-pyrrolidin-1-ylmethyl-piperidin-1-yl)-benzyl]-piperidine

[0737] Prepared from the product of Example 67 and piperidine.

[0738]¹H NMR (500 MHz, CDCl₃): 6.94-6.87 (m, 2H), 6.80 (t, J=8.6, 1H),3.35 (d, J=12.0 Hz, 2H), 3.30 (s, 2H), 2.57-2.43 (m, 2H), 2.43-2.27 (m,11H), 1.73-1.70 (m, 6H), 1.51-1.34 (m, 8H).

Example 81

[0739]

[0740]13-[4-(4-pyrrolidin-1-ylmethyl-piperidin-1-yl)-2-trifluoromethyl-benzyl]-1,4,7,10-tetraoxa-13-aza-cyclopentadecaneDitrifluoromethanesulfonate

[0741] Prepared from the product of Example 65 and1,4,7,10-tetraoxa-13-aza-cyclopentadecane. The crude material waspurified by HPLC (Column: Phenomenex, Synergi Max-RP C-12; 4 micronparticle size; 100 mm×21.2 mm (ID) mm. Gradient System: 10% water:acetonitrile to 99% water:acetonitrile containing 0.05% TFA over 0-19minutes) to provide the target compound as theditrifluoromethanesulfonate salt.

[0742]¹H NMR (500 MHz, CD₃OD): 7.68 (d, J=8.7 Hz, 1H), 7.29 (d, J=2.6Hz, 1H), 7.26 (dd, J=8.7, 2.6 Hz, 1H), 3.95-2.92 (m, 31H), 2.17-1.93 (m,8H), 1.45-1.40 (m, 2H).

Example 82

[0743]

[0744]{1-[4-(4-Pyrrolidin-1-ylmethyl-piperidin-1-yl)-3-trifluoromethyl-benzyl]-piperidin-4-yl}-methanol

[0745] Prepared from the product of Example 63 and4-hydroxymethylpiperidine.

[0746]¹H NMR (500 MHz, CDCl₃): 7.78-7.14 (m, 3H), 4.30-4.11 (m, 1H),3.52-3.44 (m, 2H), 3.15-2.49 (m, 7H), 2.06-1.60 (m, 11H), 1.56-0.75 (m,12H).

Biological Methods

[0747] In Vitro

[0748] Transfection of cells with human histamine receptor A 10 cmtissue culture dish with a confluent monolayer of SK-N-MC cells wassplit two days prior to transfection. Using sterile technique the mediawas removed and the cells were detached from the dish by the addition oftrypsin. One fifth of the cells were then placed onto a new 10 cm dish.Cells were grown in a 37° C. incubator with 5% CO₂ in Minimal EssentialMedia Eagle with 10% Fetal Bovine Serum. After two days cells wereapproximately 80% confluent. These were removed from the dish withtrypsin and pelleted in a clinical centrifuge. The pellet was thenre-suspended in 400 μL complete media and transferred to anelectroporation cuvette with a 0.4 cm gap between the electrodes. Onemicrogram of supercoiled H₃ receptor cDNA was added to the cells andmixed. The voltage for the electroporation was set at 0.25 kV, thecapacitance was set at 960 μF. After electroporation the cells werediluted into 10 mL complete media and plated onto four 10 cm dishes.Because of the variability in the efficiency of electroporation, fourdifferent concentrations of cells were plated. The ratios used were;1:20, 1:10, 1:5, with the remainder of the cells being added to thefourth dish. The cells were allowed to recover for 24 h before addingthe selection media (complete media with 600 μg/mL G418). After 10 daysdishes were analyzed for surviving colonies of cells. Dishes withwell-isolated colonies were used. Cells from individual colonies wereisolated and tested. SK-N-MC cells were used because they give efficientcoupling for inhibition of adenylate cyclase. The clones that gave themost robust inhibition of adenylate cyclase in response to histaminewere used for further study.

[0749] {³H}-N-methylhistamine Binding

[0750] Cell pellets from histamine H₃ receptor-expressing SK-N-MC cellswere homogenized in 20 mM Tris HCl/0.5 mM EDTA. Supernatants from an 800g spin were collected, recentrifuged at 30,000 g for 30 min. Pelletswere re-homogenized in 50 mM Tris/5 mM EDTA (pH 7.4). Membranes wereincubated with 0.8 nM {³H}-N-methylhistamine plus/minus test compoundsfor 45 min at 25° C. and harvested by rapid filtration over GF/C glassfiber filters (pretreated with 0.3% polyethylenimine) followed by fourwashes with ice-cold buffer. Filters were dried, added to 4 mLscintillation cocktail and then counted on a liquid scintillationcounter. Non-specific binding was defined with 10 μM histamine. ThepK_(i) values were calculated based on a K_(d) of 800 pM and a ligandconcentration ({L}) of 800 pM according to the formula:

K _(i)=(IC ₅₀)/(1+({L}/(K _(d)))

[0751] K_(i) values for exemplary compounds of the invention are listedin the below: EX K_(i) (nM) 22 4500 23 0.9 24 23 25 0.8 26 1.7 27 1.4 280.8 29 2 30 1.0 31 2.0 32 9.0 33 20 34 6.0 35 10 36 6.0 37 2.0 38 5.0 396.0 40 4.0 41 12 42 5.0 43 4800 44 5.0 45 2.0 46 28 47 5.8 48 1000 49 1450 272 51 17 52 5.5 53 2.7 54 8.4 55 8.0 56 3.0 57 2.5 58 0.6 59 48 601.1 61 0.8 62 1.3 68 14 69 2 70 36 71 5 72 8 73 16 74 1 75 6 76 9 77 16078 7 79 4 80 4 81 34 82 170

F. Other Embodiments

[0752] The features and advantages of the invention will be apparent toone of ordinary skill in view of the discussion, examples, embodiments,and claims relating to the invention. The invention also contemplatesvariations and adaptations, based on the disclosure herein concerningthe key features and advantages of the invention, and within theabilities of one of ordinary skill.

What is claimed is:
 1. A composition comprising a compound of formula(I):

wherein L is a direct bond, or an optionally C₁₋₄alkyl substitutedradical selected from the group consisting of C₁₋₄alkylene orC₃₋₄alkenylene wherein NR¹R² is attached to an sp³ hybridized carbon,C₃₋₄alkynylene wherein NR¹R² is attached to an sp³ hybridized carbon,C₂₋₄alkylidene wherein NR¹R² is attached to an sp³ hybridized carbon,aryloxy wherein NR¹R² is not attached to the oxygen, arylthio whereinNR¹R² is not attached to the sulfur, C₂₋₄alkoxy wherein NR¹R² is notattached to the oxygen or a carbon attached to the oxygen, C₂₋₄alkylthiowherein NR¹R² is not attached to the sulfur or a carbon attached to thesulfur, and —C₂₋₃alkyl-X—C₁₋₂alkyl- wherein X is O, S or NH and whereinNR¹R² is not attached to a carbon attached to X; p is 0, 1 or 2; q is 1or 2; provided that 2<p+q<4; R¹ is a substituent independently selectedfrom the group consisting of hydrogen, C₁₋₆ alkyl, C₃₋₆ alkenyl, C₃₋₉carbocyclyl, 3-12 membered heterocyclyl, phenyl, (5-9-memberedheterocyclyl)C₁₋₆ alkylene, and (phenyl)C₁₋₆ alkylene; R is asubstituent independently selected from the group consisting of C₁₋₆alkyl, C₃₋₆ alkenyl, C₃₋₉ membered carbocyclyl, 3-12 memberedheterocyclyl, phenyl, (5-9-membered heterocyclyl)C₁₋₆ alkylene, and(phenyl)C₁₋₆ alkylene; or R¹ and R² taken together with the nitrogen towhich they are attached form a saturated 3-13 membered N-linkedheterocyclyl, wherein, in addition to the N-linking nitrogen, the 3-13membered heterocyclyl may optionally contain between 1 and 3 additionalheteroatoms independently selected from O, S, and NH; wherein R¹ and R²are optionally and independently substituted with 1-3 substituentsselected from the group consisting of tert-butyloxycarbonyl, hydroxy,halo, nitro, amino, cyano, carboxamide, C₁₋₆ alkyl, C₁₋₆ acyl,5-9-membered heterocyclyl, —N(C₁₋₆ alkyl)(5-9 membered heterocyclyl),—NH(5-9 membered heterocyclyl), —O(5-9 membered heterocyclyl), (5-9membered heterocyclyl)C₁₋₃ alkylene, C₁₋₂-hydroxyalkylene, C₁₋₆ alkoxy,(C₃₋₆ cycloalkyl)-O—, phenyl, (phenyl)C₁₋₃ alkylene, and (phenyl)C₁₋₃alkylene-O—; and wherein each of the preceding substituents of R¹ and R²may optionally have between 1 and 3 substituents independently selectedfrom the group consisting of trifluoromethyl, halo, nitro, cyano,hydroxy, and C₁₋₃ alkyl; one of R³, R⁴ and R⁵ is G and the other twoindependently are hydrogen, fluoro, chloro, bromo, nitro,trifluoromethyl, methyl, or C₁₋₃ alkoxy; G is L²Q; L² is unbranched—(CH₂)_(n)— wherein n is an integer from 1 to 7; Q is NR⁸R⁹ wherein R⁸is independently selected from hydrogen, C₁₋₆ alkyl, C₃₋₆ alkenyl, C₃₋₉carbocyclyl, 3-12 membered heterocyclyl, phenyl, (5-9-memberedheterocyclyl)C₁₋₆ alkylene, and (phenyl)C₁₋₆ alkylene; and R⁹ isindependently selected from C₁₋₆ alkyl, C₃₋₆ alkenyl, 3-9 memberedcarbocyclyl, 3-13 membered heterocyclyl, phenyl, (5-9-memberedheterocyclyl)C₁₋₆ alkylene, and (phenyl)C₁₋₆ alkylene; or Q is asaturated 3-15 membered N-linked heterocyclyl, wherein, in addition tothe N-linking nitrogen, the 3-15 membered heterocyclyl may optionallycontain between 1 and 4 additional heteroatoms independently selectedfrom O, S, and NH; wherein Q is optionally substituted with 1-3substituents selected (in addition to the preceding paragraph) from thegroup consisting of tert-butyloxycarbonyl, hydroxy, halo, nitro, amino,cyano, carboxamide, C₁₋₆ alkyl, C₁₋₆ acyl, 5-9-membered heterocyclyl,—N(C₁₋₆ alkyl)(5-9 membered heterocyclyl), —NH(5-9 memberedheterocyclyl), —O(5-9 membered heterocyclyl), (5-9 memberedheterocyclyl)C₁₋₃ alkylene, C₁₋₂-hydroxyalkylene, C₁₋₆ alkoxy, (C₃₋₆cycloalkyl)-O—, phenyl, (phenyl)C₁₋₃ alkylene, and (phenyl)C₁₋₃alkylene-O—; and where said substituent groups of Q may optionally havebetween 1 and 3 substituents independently selected fromtrifluoromethyl, halo, nitro, cyano, hydroxy, and C₁₋₃ alkyl; R^(a) areindependently C₁₋₃ alkyl, triflouromethyl; m is 0, 1, 2 or 3; andwherein each of the above alkyl, alkylene, alkenyl, heterocyclyl,cycloalkyl, carbocyclyl, and aryl groups may each be independently andoptionally substituted with between 1 and 3 substituents independentlyselected from methoxy, halo, amino, nitro, hydroxy, and C₁₋₃ alkyl; or apharmaceutically acceptable salt, ester, tautomer, solvate or amidethereof.
 2. A compound of claim 1, wherein NR¹R² taken together formsubstituted or unsubstituted morpholinyl, thiomorpholinyl, piperidinyl,methylpiperidinyl, piperazinyl, N-methylpiperazinyl, dimethylamino,pyrrolidinyl, azatricyclodecanyl, cyclohexylmethylamino,methylphenethylamino, pyridylamino, anilino, diethylamino,methylethylamino, ethylpropylamino, or dipropylamino;
 3. A compound ofclaim 1, wherein NR¹R² taken together form a saturated N-linkednitrogen-containing heterocyclyl.
 4. A compound of claim 1, whereinNR¹R² taken together form a substituent selected from substituted orunsubstituted piperidinyl, substituted or unsubstituted piperazinyl,pyrrolinyl, pyrrolidinyl, thiomorpholinyl, and morpholinyl.
 5. Acompound of claim 1, wherein wherein NR¹R² taken together form asubstituent selected from N-(C₁₋₆ alkyl)piperazinyl,N-phenyl-piperazinyl, 1,3,8-triaza-spiro{4.5}decyl, and1,4-dioxa-8-aza-spiro{4.5}decyl.
 6. A compound of claim 2, wherein NR¹R²taken together form a monovalent radical of an amine selected from thegroup consisting of aziridine, 1,4,7-trioxa-10-aza-cyclododecane,thiazolidine, 1-phenyl-1,3,8-triaza-spiro{4.5}decan-4-one,piperidine-3-carboxylic acid diethylamide,1,2,3,4,5,6-hexahydro-{2,3′}bipyridinyl,4-(3-trifluoromethyl-phenyl)-piperazine, 2-piperazin-1-yl-pyrimidine,piperidine-4-carboxylic acid amide, methyl-(2-pyridin-2-yl-ethyl)-amine,{2-(3,4-dimethoxy-phenyl)-ethyl}-methyl-amine, thiomorpholinyl,allyl-cyclopentyl-amine, {2-(1H-indol-3-yl)-ethyl}-methyl-amine,1-piperidin-4-yl-1,3-dihydro-benzoimidazol-2-one,2-(piperidin-4-yloxy)-pyrimidine, piperidin-4-yl-pyridin-2-yl-amine,phenylamine, pyridin-2-ylamine.
 7. A compound of claim 4, wherein NR¹R²taken together form a substituent selected from the group consisting ofmorpholinyl and piperidinyl, wherein said substituent is optionallysubstituted with between 1 and 3 substituents selected from hydroxy,halo, carboxamide, C₁₋₆ alkyl, C₁₋₆ acyl, 5-9 membered heterocyclyl,—N(C₁₋₆ alkyl)(5-9 membered heterocyclyl), —NH(5-9 memberedheterocyclyl), —O(5-9 membered heterocyclyl), (5-9 memberedheterocyclyl)C₁₋₃ alkylene, C₁₋₂-hydroxyalkylene, C₁₋₆ alkoxy, (C₃₋₆cycloalkyl)-O—, phenyl, (phenyl)C₁₋₃ alkylene, and (phenyl)C₁₋₃alkylene-O— where each of above heterocyclyl, phenyl, and alkyl groupsmay be optionally substituted with from 1 to 3 substituentsindependently selected from trifluoromethyl, halo, nitro, cyano,hydroxy, and C₁₋₃ alkyl.
 8. A compound of claim 3, wherein the saturatedN-linked nitrogen-containing heterocyclyl is substituted with asubstituent selected from the group consisting of pyridyl, pyrimidyl,furyl, thiofuryl, imidazolyl, (imidazolyl)C₁₋₆ alkylene, oxazolyl,thiazolyl, 2,3-dihydro-indolyl, benzimidazolyl, 2-oxobenzimidazolyl,(tetrazolyl)C₁₋₆ alkylene, tetrazolyl, (triazolyl)C₁₋₆ alkylene,triazolyl, (pyrrolyl)C₁₋₆ alkylene, pyrrolidinyl, and pyrrolyl.
 9. Acompound of claim 1, wherein NR¹R² taken together form morpholinyl,piperidinyl, pyrrolidinyl, or diethylamino.
 10. A compound of claim 1,wherein Q is morpholinyl, piperidinyl, pyrrolidinyl, or diethylamino.11. A compound of claim 1, wherein NR¹R² taken together formmorpholinyl, piperidinyl, or pyrrolidinyl.
 12. A compound of claim 1,wherein Q is morpholinyl, piperidinyl, or pyrrolidinyl.
 13. A compoundof claim 12, wherein NR¹R² is a substituted or unsubstituted morpholino.14. A compound of claim 1, wherein one of R³ and R⁴ is G.
 15. A compoundof claim 1, wherein R⁴ is G.
 16. A compound of claim 14, wherein R³ isG.
 17. A compound of claim 1, wherein q is 2 and p is
 1. 18. A compoundof claim 1, wherein q is 1 and p is
 1. 19. A compound of claim 1,wherein q is 2 and p is
 2. 20. A compound of claim 1, wherein L is—CH₂—.
 21. A compound of claim 1, wherein L is a direct bond.
 22. Acompound of claim 1, wherein L is —CH₂CH₂—.
 23. A compound of claim 1,wherein L² is —CH₂—
 24. A compound of claim 1, wherein Q is selectedfrom the group consisting of substituted or unsubstituted pyrrolidinyl,piperidinyl, methylpiperidinyl, morpholinyl, thiomorpholinyl,azatricyclodecanyl, cyclohexylamino, cyclohexylmethylamino, piperazinyl,N-methylpiperazinyl, dimethylamino, methylphenethylamino, pyridylamino,anilino, diethylamino, methylethylamino, ethylpropylamino,dipropylamino, or 1,4,7,10-tetraoxa-13-aza-cyclopentadecanyl.
 25. Acompound of claim 1, wherein Q is a saturated N-linkednitrogen-containing heterocyclyl.
 26. A compound of claim 1, wherein Qis a substituent selected from the group consisting of substitutedpiperidinyl, unsubstituted piperidinyl, substituted piperazinyl,unsubstituted piperazinyl, pyrrolinyl, pyrrolidinyl, thiomorpholinyl,and morpholinyl.
 27. A compound of claim 1, wherein substituted Q isN-(C₁₋₆ alkyl)piperazinyl, N-phenyl-piperazinyl,1,3,8-triaza-spiro{4.5}decyl, or 1,4-dioxa-8-aza-spiro{4.5}decyl.
 28. Acompound of claim 25, wherein Q is a monovalent radical of an amineselected from the group consisting of aziridine,1,4,7-trioxa-10-aza-cyclododecane, thiazolidine,1-phenyl-1,3,8-triaza-spiro{4.5}decan-4-one, piperidine-3-carboxylicacid diethylamide, 1,2,3,4,5,6-hexahydro-{2,3′}bipyridinyl,4-(3-trifluoromethyl-phenyl)-piperazine, 2-piperazin-1-yl-pyrimidine,piperidine-4-carboxylic acid amide, methyl-(2-pyridin-2-yl-ethyl)-amine,{2-(3,4-dimethoxy-phenyl)-ethyl}-methyl-amine, thiomorpholinyl,allyl-cyclopentyl-amine, {2-(1H-indol-3-yl)-ethyl}-methyl-amine,1-piperidin-4-yl-1,3-dihydro-benzoimidazol-2-one,2-(piperidin-4-yloxy)-pyrimidine, piperidin-4-yl-pyridin-2-yl-amine,phenylamine, and pyridin-2-ylamine.
 29. A compound of claim 25, whereinQ is morpholinyl, pyridyl, or piperidinyl, and wherein Q is optionallysubstituted with between 1 and 3 substituents selected from hydroxy,halo, carboxamide, C₁₋₆ alkyl, C₁₋₆ acyl, 5-9 membered or 6-9 memberedheterocyclyl, —N(C₁₋₆ alkyl)(5-9 membered or 6-9 membered heterocyclyl),—NH(5-9 membered or 6-9 membered heterocyclyl), —O(5-9 or 6-9 memberedheterocyclyl), (5-9 membered or 6-9 membered heterocyclyl)C₁₋₃ alkylene,C₁₋₂-hydroxyalkylene, C₁₋₆ alkoxy, (C₃₋₆ cycloalkyl)-O—, phenyl,(phenyl)C₁₋₃ alkylene, and (phenyl)C₁₋₃ alkylene-O— where each of aboveheterocyclyl, phenyl, and alkyl groups may be optionally substitutedwith from 1 to 3 substituents independently selected fromtrifluoromethyl, halo, nitro, cyano, hydroxy, and C₁₋₃ alkyl.
 30. Acompound of claim 29, wherein Q is substituted with a substituentcomprising a 5-9 membered heterocyclyl group selected from: pyridyl,pyrimidyl, furyl, thiofuryl, imidazolyl, (imidazolyl)C₁₋₆ alkylene,oxazolyl, thiazolyl, 2,3-dihydro-indolyl, benzimidazolyl,2-oxobenzimidazolyl, (tetrazolyl)C₁₋₆ alkylene, tetrazolyl,(triazolyl)C₁₋₆ alkylene, triazolyl, (pyrrolyl)C₁₋₆ alkylene,pyrrolidinyl, and pyrrolyl.
 31. A compound of claim 30, wherein Q is asubstituted or unsubstituted morpholinyl. 32 A compound of claim 1,wherein R⁸ is hydrogen.
 33. A compound of claim 1, wherein R⁸ is C₁₋₆alkyl.
 34. A compound of claim 1, wherein R⁸ is cyclohexyl.
 35. Acompound of claim 1, wherein R⁸ and R⁹ independently are C₁₋₆ alkyl. 36.A compound of claim 1, wherein R⁸ and R⁹ are methyl.
 37. A compound ofclaim 1, wherein R⁸ and R⁹ are ethyl.
 38. A compound of claim 32,wherein R⁹ is selected from phenyl or 5-9 membered aromaticheterocyclyl, wherein said phenyl or aromatic heterocyclyl is optionallysubstituted with 1-3 substituents selected from hydroxy, halo, nitro,cyano, trifluoromethyl, and C₁₋₃ alkyl.
 39. A compound of claim 38,wherein R⁹ is selected from substituted or unsubstituted phenyl,pyridyl, pyrimidyl, furyl, thiofuryl, imidazolyl, (imidazolyl)C₁₋₆alkylene, oxazolyl, thiazolyl, 2,3-dihydro-indolyl, benzimidazolyl,2-oxobenzimidazolyl, (tetrazolyl)C₁₋₆ alkylene, tetrazolyl,(triazolyl)C₁₋₆ alkylene, triazolyl, (pyrrolyl)C₁₋₆ alkylene, andpyrrolyl.
 40. A compound of claim 39, wherein R⁹ is substituted orunsubstituted phenyl.
 41. A compound of claim 39, wherein R⁹ issubstituted or unsubstituted pyridyl.
 42. A compound of claim 1,wherein: R¹and R² are independently selected from C₂ alkyl, or takentogether with the nitrogen to which they are attached, they form anon-aromatic 5-6 membered heterocyclyl optionally including anadditional heteroatom independently selected from O, S, and NH; one ofR³, R⁴, and R⁵ is G and the two remaining are H; G is L²Q; L² ismethylene; Q is NR⁸R⁹ wherein R⁸ is independently selected fromhydrogen, C₁₋₂ alkyl, C₃ alkenyl, C₅₋₉ carbocyclyl, 3-12 memberedheterocyclyl, phenyl, (5-9-membered heterocyclyl)C₁₋₆ alkylene, and(phenyl)C₁₋₆ alkylene; and R⁹ is independently selected from C₁₋₂ alkyl,C₃ alkenyl, C₅₋₉ carbocyclyl, 3-12 membered heterocyclyl, phenyl,(6-9-membered heterocyclyl)C₁₋₆ alkylene, and (phenyl)C₁₋₆ alkylene; orQ is a saturated 3-15 membered N-linked heterocyclyl, wherein, inaddition to the N-linking nitrogen, the 3-15 membered heterocyclyl mayoptionally contain between 1 and 4 additional heteroatoms selected fromO, S, and NH; wherein each of the above alkyl, alkylene, alkenyl,alkenylene, heterocyclyl, and carbocyclyl groups may each beindependently and optionally substituted with between 1 and 3substituents selected from methoxy, halo, amino, nitro, hydroxyl, andC₁₋₃ alkyl; wherein substituents of Q can be further selected fromtert-butyloxycarbonyl, hydroxy, halo, nitro, amino, cyano, carboxamide,5-9-membered heterocyclyl, —NH(6-membered heterocyclyl), —O(6-memberedheterocyclyl), C₂-hydroxyalkylene, phenyl, benzyl and, where each ofabove heterocyclyl, phenyl, and alkyl substituent groups of Q may beoptionally substituted with trifluoromethyl; or a pharmaceuticallyacceptable salt, ester, tautomer, solvate or amide thereof.
 43. Acompound of claim 1, wherein NR¹R² taken together form morpholinyl,piperidinyl, pyrrolidinyl, or diethylamino, p is 1 and q is 2, and Q isselected from substituted or unsubstituted piperidinyl, piperazinyl,pyrrolinyl, pyrrolidinyl, thiomorpholinyl, and morpholinyl.
 44. Acompound of claim 1, wherein (a) NR¹R² taken together form piperidinylor pyrrolidinyl, (b) n is 1, (c) p is 1 and q is 2, and (d) Q isselected from morpholinyl and piperidinyl.
 45. A compound of claim 1,wherein (a) NR¹R² taken together form piperidinyl or pyrrolidinyl, (b) nis 1, (c) p is 1 and q is 2, and (d) Q is selected from morpholinyl andpiperidinyl.
 46. A compound of claim 44, wherein Q is piperidinyl orsubstituted piperidinyl.
 47. A compound of claim 1, wherein NR¹R² takentogether form piperidinyl, pyrrolidinyl, or diethylamino, n is 1, p is 1and q is 2, and Q is NR⁸R⁹ and R⁸ is H and R⁹ is selected from phenyl oraromatic 5-9 membered heterocyclyl, wherein said phenyl or heterocyclylis optionally substituted with 1-3 substituents selected fromtrifluoromethyl, halo, nitro, cyano, hydroxy, and C₁₋₃ alkyl.
 48. Acompound of claim 1 wherein R^(a) is hydrogen.
 49. A compound of claim 1selected from the group consisting of4-{2-(4-Piperidin-1-ylmethyl-piperidin-1-yl)-benzyl}-morpholine;Cyclohexyl-{1-(4-pyrrolidin-1-ylmethyl-phenyl)-piperidin-4-ylmethyl}-amine;1-{1-(4-Pyrrolidin-1-ylmethyl-phenyl)-piperidin-4-ylmethyl}-azacyclotridecane;Diethyl-{1-(4-pyrrolidin-1-ylmethyl-phenyl)-piperidin-4-ylmethyl}-amine;Dimethyl-{1-(4-pyrrolidin-1-ylmethyl-phenyl)-piperidin-4-ylmethyl}-amine;1-Methyl-4-{1-(4-pyrrolidin-1-ylmethyl-phenyl)-piperidin-4-ylmethyl}-piperazine;1-{1-(4-Pyrrolidin-1-ylmethyl-phenyl)-piperidin-4-ylmethyl}-piperidin-4-ol;4-{1-(4-Pyrrolidin-1-ylmethyl-phenyl)-piperidin-4-ylmethyl}-thiomorpholine;1-{1-(4-Pyrrolidin-1-ylmethyl-phenyl)-piperidin-4-ylmethyl}-piperidine;4-{1-(4-Pyrrolidin-1-ylmethyl-phenyl)-piperidin-4-ylmethyl}-morpholine;4-{3-(4-Pyrrolidin-1-ylmethyl-piperidin-1-yl)-benzyl}-thiomorpholine;4-{3-(4-Pyrrolidin-1-ylmethyl-piperidin-1-yl)-benzyl}-morpholine;4-Pyrrolidin-1-ylmethyl-1-(3-pyrrolidin-1-ylmethyl-phenyl)-piperidine;1-{3-(4-Pyrrolidin-1-ylmethyl-piperidin-1-yl)-benzyl}-piperidine;1-{4-(4-Pyrrolidin-1-ylmethyl-piperidin-1-yl)-benzyl}-azacyclotridecane;Cyclohexyl-{4-(4-pyrrolidin-1-ylmethyl-piperidin-1-yl)-benzyl}-amine;1-{4-(4-Pyrrolidin-1-ylmethyl-piperidin-1-yl)-benzyl}-piperidin-4-ol;1-Methyl-4-{4-(4-pyrrolidin-1-ylmethyl-piperidin-1-yl)-benzyl}-piperazine;4-{4-(4-Pyrrolidin-1-ylmethyl-piperidin-1-yl)-benzyl}-thiomorpholine;4-{4-(4-Pyrrolidin-1-ylmethyl-piperidin-1-yl)-benzyl}-morpholine;Dimethyl-{4-(4-pyrrolidin-1-ylmethyl-piperidin-1-yl)-benzyl}-amine;4-{2-(4-Pyrrolidin-1-ylmethyl-piperidin-1-yl)-benzyl}-morpholine;4-{1-(4-Piperidin-1-ylmethyl-phenyl)-piperidin-4-ylmethyl}-morpholine;1-{4-(4-Pyrrolidin-1-ylmethyl-piperidin-1-yl)-benzyl}-piperidine;Cyclohexyl-{1-(4-morpholin-4-ylmethyl-phenyl)-piperidin-4-yl}-amine;Cyclohexyl-methyl-{1-(4-morpholin-4-ylmethyl-phenyl)-piperidin-4-yl}-amine;4-{4-{4-(4-Methyl-piperazin-1-yl)-piperidin-1-yl}-benzyl}-morpholine;Ethyl-methyl-{1-(4-morpholin-4-ylmethyl-phenyl)-piperidin-4-yl}-amine;4-{1-(4-Morpholin-4-ylmethyl-phenyl)-piperidin-4-yl}-morpholine;4-{4-(4-Pyrrolidin-1-yl-piperidin-1-yl)-benzyl}-morpholine;1′-(4-Morpholin-4-ylmethyl-phenyl)-{1,4′}bipiperidinyl;1′-(4-Piperidin-1-ylmethyl-phenyl)-{1,4′}bipiperidinyl;(4-{1,4′}Bipiperidinyl-1′-yl-benzyl)-pyridin-2-yl-amine;Phenyl-{1-(4-pyrrolidin-1-ylmethyl-phenyl)-piperidin-4-ylmethyl}-amine;Pyridin-2-yl-{1-(4-pyrrolidin-1-ylmethyl-phenyl)-piperidin-4-ylmethyl}-amine;1-{1-(4-Piperidin-1-ylmethyl-phenyl)-piperidin-4-ylmethyl}-piperidine;4-Pyrrolidin-1-ylmethyl-1-(4-pyrrolidin-1-ylmethyl-phenyl)-piperidine;(4-Fluoro-phenyl)-{4-(4-pyrrolidin-1-ylmethyl-piperidin-1-yl)-benzyl}-amine;4-{2-{1-(4-Piperidin-1-ylmethyl-phenyl)-pyrrolidin-3-yl}-ethyl}-morpholine;Diethyl-{2-{1-(4-piperidin-1-ylmethyl-phenyl)-pyrrolidin-3-yl}-ethyl}-amine;Methyl-phenethyl-{2-{1-(4-piperidin-1-ylmethyl-phenyl)-pyrrolidin-3-yl}-ethyl}-amine;1-[4-(4-Pyrrolidin-1-ylmethyl-piperidin-1-yl)-3-trifluoromethyl-benzyl]-piperidine;1-(2-Nitro-4-pyrrolidin-1-ylmethyl-phenyl)-4-pyrrolidin-1-ylmethyl-piperidine;4-[3-Nitro-4-(4-pyrrolidin-1-ylmethyl-piperidin-1-yl)-benzyl]-morpholine;1-[3-Nitro-4-(4-pyrrolidin-1-ylmethyl-piperidin-1-yl)-benzyl]-piperidin-4-ol;1-[4-(4-Pyrrolidin-1-ylmethyl-piperidin-1-yl)-2-trifluoromethyl-benzyl]-piperidine;1-Isopropyl-4-[3-methyl-4-(4-pyrrolidin-1-ylmethyl-piperidin-1-yl)-benzyl]-piperazine;1-(2-Methyl-4-pyrrolidin-1-ylmethyl-phenyl)-4-pyrrolidin-1-ylmethyl-pyrrolidine;1-[3-Methyl-4-(4-pyrrolidin-1-ylmethyl-piperidin-1-yl)-benzyl]-pyrrolidine;1-{1-[4-(4-Pyrrolidin-1-yl-piperidin-1-ylmethyl)-2-trifluoromethyl-phenyl]-piperidin-4-ylmethyl}-pyrrolidine;1-(1-{3-Trifluoromethyl-4-[4-(4-trifluoromethyl-phenyl)-piperidin-1-ylmethyl]-phenyl}-piperidin-4-ylmethyl)-pyrrolidine;1-{1-[2-Fluoro-4-(4-phenyl-piperidin-1-ylmethyl)-phenyl]-piperidin-4-ylmethyl}-pyrrolidine;[3-Fluoro-4-(4-pyrrolidin-1-ylmethyl-piperidin-1-yl)-benzyl]-dimethyl-amine;1-[3-Fluoro-4-(4-pyrrolidin-1-ylmethyl-piperidin-1-yl)-benzyl]-piperidine;13-[4-(4-Pyrrolidin-1-ylmethyl-piperidin-1-yl)-2-trifluoromethyl-benzyl]-1,4,7,10-tetraoxa-13-aza-cyclopentadecaneditrifluoromethanesulfonate; and{1-[4-(4-Pyrrolidin-1-ylmethyl-piperidin-1-yl)-3-trifluoromethyl-benzyl]-piperidin-4-yl}-methanol.50. A compound of claim 1 selected from the group consisting of(4-{1,4′}Bipiperidinyl-1′-yl-benzyl)-pyridin-2-yl-amine;1′-(4-Morpholin-4-ylmethyl-phenyl)-{1,4′}bipiperidinyl;1′-(4-Piperidin-1-ylmethyl-phenyl)-{1,4′}bipiperidinyl;1-{1-(4-Piperidin-1-ylmethyl-phenyl)-piperidin-4-ylmethyl}-piperidine;4-{1-(4-Piperidin-1-ylmethyl-phenyl)-piperidin-4-ylmethyl}-morpholine;1-{1-(4-Pyrrolidin-1-ylmethyl-phenyl)-piperidin-4-ylmethyl}-piperidin-4-ol;1-{1-(4-Pyrrolidin-1-ylmethyl-phenyl)-piperidin-4-ylmethyl}-piperidine;1-{3-(4-Pyrrolidin-1-ylmethyl-piperidin-1-yl)-benzyl}-piperidine;1-{4-(4-Pyrrolidin-1-ylmethyl-piperidin-1-yl)-benzyl}-azacyclotridecane;1-{4-(4-Pyrrolidin-1-ylmethyl-piperidin-1-yl)-benzyl}-piperidin-4-ol;1-{4-(4-Pyrrolidin-1-ylmethyl-piperidin-1-yl)-benzyl}-piperidine;1-Methyl-4-{1-(4-pyrrolidin-1-ylmethyl-phenyl)-piperidin-4-ylmethyl}-piperazine;1-Methyl-4-{4-(4-pyrrolidin-1-ylmethyl-piperidin-1-yl)-benzyl}-piperazine;4-{1-(4-Pyrrolidin-1-ylmethyl-phenyl)-piperidin-4-ylmethyl}-morpholine;4-{1-(4-Pyrrolidin-1-ylmethyl-phenyl)-piperidin-4-ylmethyl}-thiomorpholine;4-{3-(4-Pyrrolidin-1-ylmethyl-piperidin-1-yl)-benzyl}-thiomorpholine;4-{4-(4-Pyrrolidin-1-ylmethyl-piperidin-1-yl)-benzyl}-thiomorpholine;4-{2-{1-(4-Piperidin-1-ylmethyl-phenyl)-pyrrolidin-3-yl}-ethyl}-morpholine;4-Pyrrolidin-1-ylmethyl-1-(3-pyrrolidin-1-ylmethyl-phenyl)-piperidine;4-Pyrrolidin-1-ylmethyl-1-(4-pyrrolidin-1-ylmethyl-phenyl)-piperidine;Cyclohexyl-{1-(4-pyrrolidin-1-ylmethyl-phenyl)-piperidin-4-ylmethyl}-amine;Cyclohexyl-{4-(4-pyrrolidin-1-ylmethyl-piperidin-1-yl)-benzyl}-amine;Cyclohexyl-methyl-{1-(4-morpholin-4-ylmethyl-phenyl)-piperidin-4-yl}-amine;Diethyl-{1-(4-pyrrolidin-1-ylmethyl-phenyl)-piperidin-4-ylmethyl}-amine;Diethyl-{2-{1-(4-piperidin-1-ylmethyl-phenyl)-pyrrolidin-3-yl}-ethyl}-amine;Dimethyl-{1-(4-pyrrolidin-1-ylmethyl-phenyl)-piperidin-4-ylmethyl}-amine;Dimethyl-{4-(4-pyrrolidin-1-ylmethyl-piperidin-1-yl)-benzyl}-amine;Methyl-phenethyl-{2-{1-(4-piperidin-1-ylmethyl-phenyl)-pyrrolidin-3-yl}-ethyl}-amine;Phenyl-{1-(4-pyrrolidin-1-ylmethyl-phenyl)-piperidin-4-ylmethyl}-amine;Pyridin-2-yl-{1-(4-pyrrolidin-1-ylmethyl-phenyl)-piperidin-4-ylmethyl}-amine;1-(2-Nitro-4-pyrrolidin-1-ylmethyl-phenyl)-4-pyrrolidin-1-ylmethyl-piperidine;1-[3-Nitro-4-(4-pyrrolidin-1-ylmethyl-piperidin-1-yl)-benzyl]-piperidin-4-ol;1-[4-(4-Pyrrolidin-1-ylmethyl-piperidin-1-yl)-2-trifluoromethyl-benzyl]-piperidine;1-(2-Methyl-4-pyrrolidin-1-ylmethyl-phenyl)-4-pyrrolidin-1-ylmethyl-pyrrolidine;1-[3-Methyl-4-(4-pyrrolidin-1-ylmethyl-piperidin-1-yl)-benzyl]-pyrrolidine;1-{1-[4-(4-Pyrrolidin-1-yl-piperidin-1-ylmethyl)-2-trifluoromethyl-phenyl]-piperidin-4-ylmethyl}-pyrrolidine;1-{1-[2-Fluoro-4-(4-phenyl-piperidin-1-ylmethyl)-phenyl]-piperidin-4-ylmethyl}-pyrrolidine;[3-Fluoro-4-(4-pyrrolidin-1-ylmethyl-piperidin-1-yl)-benzyl]-dimethyl-amine;and1-[3-Fluoro-4-(4-pyrrolidin-1-ylmethyl-piperidin-1-yl)-benzyl]-piperidine.51. A compound of claim 1 selected from the group consisting of1′-(4-Piperidin-1-ylmethyl-phenyl)-{1,4′}bipiperidinyl;1-{1-(4-Piperidin-1-ylmethyl-phenyl)-piperidin-4-ylmethyl}-piperidine;4-{1-(4-Piperidin-1-ylmethyl-phenyl)-piperidin-4-ylmethyl}-morpholine;1-{1-(4-Pyrrolidin-1-ylmethyl-phenyl)-piperidin-4-ylmethyl}-piperidin-4-ol;1-{1-(4-Pyrrolidin-1-ylmethyl-phenyl)-piperidin-4-ylmethyl}-piperidine;1-{4-(4-Pyrrolidin-1-ylmethyl-piperidin-1-yl)-benzyl}-piperidin-4-ol;1-{4-(4-Pyrrolidin-1-ylmethyl-piperidin-1-yl)-benzyl}-piperidine;1-Methyl-4-{1-(4-pyrrolidin-1-ylmethyl-phenyl)-piperidin-4-ylmethyl}-piperazine;4-{1-(4-Pyrrolidin-1-ylmethyl-phenyl)-piperidin-4-ylmethyl}-morpholine;4-{1-(4-Pyrrolidin-1-ylmethyl-phenyl)-piperidin-4-ylmethyl}-thiomorpholine;4-{4-(4-Pyrrolidin-1-ylmethyl-piperidin-1-yl)-benzyl}-thiomorpholine;4-{2-{1-(4-Piperidin-1-ylmethyl-phenyl)-pyrrolidin-3-yl}-ethyl}-morpholine;4-Pyrrolidin-1-ylmethyl-1-(4-pyrrolidin-1-ylmethyl-phenyl)-piperidine;Cyclohexyl-{1-(4-pyrrolidin-1-ylmethyl-phenyl)-piperidin-4-ylmethyl}-amine;Cyclohexyl-{4-(4-pyrrolidin-1-ylmethyl-piperidin-1-yl)-benzyl}-amine;Diethyl-{1-(4-pyrrolidin-1-ylmethyl-phenyl)-piperidin-4-ylmethyl}-amine;Diethyl-{2-{1-(4-piperidin-1-ylmethyl-phenyl)-pyrrolidin-3-yl}-ethyl}-amine;Dimethyl-{1-(4-pyrrolidin-1-ylmethyl-phenyl)-piperidin-4-ylmethyl}-amine;Dimethyl-{4-(4-pyrrolidin-1-ylmethyl-piperidin-1-yl)-benzyl}-amine;Methyl-phenethyl-{2-{1-(4-piperidin-1-ylmethyl-phenyl)-pyrrolidin-3-yl}-ethyl}-amine;Pyridin-2-yl-{1-(4-pyrrolidin-1-ylmethyl-phenyl)-piperidin-4-ylmethyl}-amine;1-(2-Nitro-4-pyrrolidin-1-ylmethyl-phenyl)-4-pyrrolidin-1-ylmethyl-piperidine;1-[3-Nitro-4-(4-pyrrolidin-1-ylmethyl-piperidin-1-yl)-benzyl]-piperidin-4-ol;1-(2-Methyl-4-pyrrolidin-1-ylmethyl-phenyl)-4-pyrrolidin-1-ylmethyl-pyrrolidine;[3-Fluoro-4-(4-pyrrolidin-1-ylmethyl-piperidin-1-yl)-benzyl]-dimethyl-amine;and1-[3-Fluoro-4-(4-pyrrolidin-1-ylmethyl-piperidin-1-yl)-benzyl]-piperidine.52. A compound of claim 1 selected from the group consisting of1-{1-(4-Pyrrolidin-1-ylmethyl-phenyl)-piperidin-4-ylmethyl}-piperidin-4-ol;1-{1-(4-Pyrrolidin-1-ylmethyl-phenyl)-piperidin-4-ylmethyl}-piperidine;1-Methyl-4-{1-(4-pyrrolidin-1-ylmethyl-phenyl)-piperidin-4-ylmethyl}-piperazine;1-{4-(4-Pyrrolidin-1-ylmethyl-piperidin-1-yl)-benzyl}-piperidine;4-{1-(4-Pyrrolidin-1-ylmethyl-phenyl)-piperidin-4-ylmethyl}-morpholine;4-{1-(4-Pyrrolidin-1-ylmethyl-phenyl)-piperidin-4-ylmethyl}-thiomorpholine;4-{2-{1-(4-Piperidin-1-ylmethyl-phenyl)-pyrrolidin-3-yl}-ethyl}-morpholine;4-Pyrrolidin-1-ylmethyl-1-(4-pyrrolidin-1-ylmethyl-phenyl)-piperidine;Cyclohexyl-{1-(4-pyrrolidin-1-ylmethyl-phenyl)-piperidin-4-ylmethyl}-amine;Cyclohexyl-{4-(4-pyrrolidin-1-ylmethyl-piperidin-1-yl)-benzyl}-amine;Diethyl-{1-(4-pyrrolidin-1-ylmethyl-phenyl)-piperidin-4-ylmethyl}-amine;Diethyl-{2-{1-(4-piperidin-1-ylmethyl-phenyl)-pyrrolidin-3-yl}-ethyl}-amine;Dimethyl-{1-(4-pyrrolidin-1-ylmethyl-phenyl)-piperidin-4-ylmethyl}-amine;Methyl-phenethyl-{2-{1-(4-piperidin-1-ylmethyl-phenyl)-pyrrolidin-3-yl}-ethyl}-amine;1-(2-Nitro-4-pyrrolidin-1-ylmethyl-phenyl)-4-pyrrolidin-1-ylmethyl-piperidine;and1-(2-Methyl-4-pyrrolidin-1-ylmethyl-phenyl)-4-pyrrolidin-1-ylmethyl-pyrrolidine.53. A compound of claim 1 selected from the group consisting of1-{1-(4-Pyrrolidin-1-ylmethyl-phenyl)-piperidin-4-ylmethyl}-piperidin-4-ol;1-{1-(4-Pyrrolidin-1-ylmethyl-phenyl)-piperidin-4-ylmethyl}-piperidine;4-Pyrrolidin-1-ylmethyl-1-(4-pyrrolidin-1-ylmethyl-phenyl)-piperidine;4-{2-{1-(4-Piperidin-1-ylmethyl-phenyl)-pyrrolidin-3-yl}-ethyl}-morpholine;Cyclohexyl-{1-(4-pyrrolidin-1-ylmethyl-phenyl)-piperidin-4-ylmethyl}-amine;Diethyl-{1-(4-pyrrolidin-1-ylmethyl-phenyl)-piperidin-4-ylmethyl}-amine;Diethyl-{2-{1-(4-piperidin-1-ylmethyl-phenyl)-pyrrolidin-3-yl}-ethyl}-amine;and1-(2-Methyl-4-pyrrolidin-1-ylmethyl-phenyl)-4-pyrrolidin-1-ylmethyl-pyrrolidine.54. A pharmaceutical composition, comprising a compound of claim 1 and apharmaceutically-acceptable excipient.
 55. A compound of claim 1isotopically-labelled to be detectable by PET or SPECT.
 56. A method ofinhibiting histamine H₃ receptor activity in a subject, comprisingadministering an effective amount of a compound of claim 1 to a subjectin need of such inhibition of histamine H₃ receptor activity.
 57. Amethod of treating a subject having a disease or condition modulated byhistamine H₃ receptor activity, comprising administering to the subjecta therapeutically effective amount of a compound of claim
 1. 58. Amethod of claim 57, wherein said disease or condition is selected fromthe group consisting of sleep/wake disorders, arousal/vigilancedisorders, migraine, asthma, dementia, mild cognitive impairment(pre-dementia), Alzheimer's disease, epilepsy, narcolepsy, eatingdisorders, motion sickness, vertigo, attention deficit hyperactivitydisorders, learning disorders, memory retention disorders,schizophrenia, nasal congestion, allergic rhinitis, and upper airwayallergic response.
 59. A method for treating a disease or conditionmodulated by at least one receptor selected from the histamine H₁receptor and the histamine H₃ receptor, said method comprising (a)administering to a subject a jointly effective amount of a histamine H₁receptor antagonist compound, and (b) administering to the subject ajointly effective amount of a compound of claim 1, said method providinga jointly therapeutically effective amount of said compounds.
 60. Themethod of claim 59 wherein the histamine H₁ receptor antagonist and thecompound of claim 1 are present in the same dosage form.
 61. A methodfor treating diseases or conditions modulated by at least one receptorselected from the histamine H₂ receptor and the histamine H₃ receptor ina subject, comprising (a) administering to the subject a jointlyeffective amount of a histamine H₂ receptor antagonist compound, and (b)administering to the subject a jointly effective amount of a compound ofclaim 1, said method providing a jointly therapeutically effectiveamount of said compounds.
 62. The method of claim 39 wherein thehistamine H₂ receptor antagonist and the compound of claim 1 are presentin the same dosage form.
 63. A method for treating one or more disordersor conditions selected from the group consisting of sleep/wakedisorders, narcolepsy, and arousal/vigilance disorders, comprisingadministering to a subject a therapeutically effective amount of acompound of claim
 1. 64. A method for treating attention deficithyperactivity disorders (ADHD), comprising administering to a subject atherapeutically effective amount of a compound of claim
 1. 65. A methodfor treating one or more disorders or conditions selected from the groupconsisting of dementia, mild cognitive impairment (pre-dementia),cognitive dysfunction, schizophrenia, depression, manic disorders,bipolar disorders, and learning and memory disorders, comprisingadministering to a subject a therapeutically effective amount of acompound of claim
 1. 66. A method for treating or preventing upperairway allergic response, nasal congestion, or allergic rhinitis,comprising administering to a subject a therapeutically effective amountof a compound of claim
 1. 67. A method for studying disorders mediatedby the histamine H₃ receptor, comprising using an ¹⁸F-labeled or¹¹C-labeled compound of claim 1 as a positron emission tomography (PET)molecular probe.
 68. A composition comprising a compound of formula (I):

wherein L is a direct bond, or an optionally C₁₋₄alkyl substitutedradical selected from the group consisting of C₁₋₄alkylene orC₃₋₄alkenylene wherein NR¹R² is attached to an sp³ hybridized carbon,C₃₋₄alkynylene wherein NR¹R² is attached to an sp³ hybridized carbon,C₂₋₄alkylidene wherein NR¹R² is attached to an sp³ hybridized carbon,aryloxy wherein NR¹R² is not attached to the oxygen, arylthio whereinNR¹R² is not attached to the sulfur, C₂₋₄alkoxy wherein NR¹R² is notattached to the oxygen or a carbon attached to the oxygen, C₂₋₄alkylthiowherein NR¹R² is not attached to the sulfur or a carbon attached to thesulfur, and —C₂₋₃alkyl-X—C₁₋₂alkyl- wherein X is O, S or NH and whereinNR¹R² is not attached to a carbon attached to X; p is 0, 1 or 2; q is 1or 2; provided that 2<p+q<4; R¹ and R² are independently selected fromhydrogen, C₁₋₃ alkyl, allyl, C₃₋₈ cycloalkyl, 5-9 membered heterocyclyl,phenyl, and (phenyl)C₁₋₃ alkylene, or taken together with the nitrogento which they are attached, they form a non-aromatic 4-13 memberedheterocyclyl optionally including up to two additional heteroatomsindependently selected from O, S, and NH; and wherein R¹ and R² areoptionally and independently substituted with substitutents selectedfrom the group consisting of trifluoromethyl, halo, nitro, cyano,hydroxy, and C₁₋₃ alkyl; one of R³, R⁴ and R⁵ is G and the other twoindependently are hydrogen, fluoro, chloro, bromo, nitro,trifluoromethyl, methyl, or C₁₋₃ alkoxy; G is L²Q; L² is unbranched—(CH₂)_(n)— wherein n is an integer from 1 to 7; Q is NR⁸R⁹ wherein R⁸is independently selected from hydrogen, C₁₋₆ alkyl, C₃₋₆ alkenyl, C₄₋₉carbocyclyl, 3-12 membered heterocyclyl, phenyl, (5-9-memberedheterocyclyl)C₁₋₆ alkylene, and (phenyl)C₁₋₆ alkylene; and R⁹ isindependently selected from C₁₋₆ alkyl, C₃₋₆ alkenyl, C₄₋₉ memberedcarbocyclyl, 3-12 membered heterocyclyl, phenyl, (5-9-memberedheterocyclyl)C₁₋₆ alkylene, and (phenyl)C₁₋₆ alkylene; or Q is asaturated 3-15 membered N-linked heterocyclyl, wherein, in addition tothe N-linking nitrogen, the 3-15 membered heterocyclyl may optionallycontain between 1 and 4 additional heteroatoms independently selectedfrom O, S, and NH; and wherein Q is optionally substituted with 1-3substituents selected (in addition to the preceding paragraph) from thegroup consisting of tert-butyloxycarbonyl, hydroxy, halo, nitro, amino,cyano, carboxamide, C₁₋₆ alkyl, C₁₋₆ acyl, 5-9-membered heterocyclyl,—N(C₁₋₆ alkyl)(5-9 membered heterocyclyl), —NH(5-9 memberedheterocyclyl), —O(5-9 membered heterocyclyl), (5-9 memberedheterocyclyl)C₁₋₃ alkylene, C₁₋₂-hydroxyalkylene, C₁₋₆ alkoxy, (C₃₋₆cycloalkyl)-O—, phenyl, (phenyl)C₁₋₃ alkylene, and (phenyl)C₁₋₃alkylene-O—; and where said substituent groups of Q may optionally havebetween 1 and 3 substituents independently selected fromtrifluoromethyl, halo, nitro, cyano, hydroxy, and C₁₋₃ alkyl; R^(a) areindependently C₁₋₃ alkyl, triflouromethyl; and m is 0, 1, 2 or 3; or apharmaceutically acceptable salt, ester, tautomer, solvate or amidethereof.